2-Phenylethylamino Derivatives as Calcium and/or Sodium Channel Modulators

ABSTRACT

2-Phenylethylamino substituted carboxamide derivatives of formula (I); wherein J, W, R 0 , R 1 , R 2 , R 3 , and R 4  have the meanings as defined in the specification and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them as active ingredient and their use as sodium and/or calcium channel modulators useful in preventing alleviating and curing a wide range of pathologies, including neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urology, and gastrointestinal diseases where the above mechanisms have been described as playing a pathological role, are described.

The present invention relates to phenylethylamino derivatives,pharmaceutically acceptable salts thereof, pharmaceutical compositionscontaining them and their use as sodium and/or calcium channelmodulators.

The phenylethylamino derivatives, object of the invention, are active ascalcium and/or sodium channel modulators and therefore useful inpreventing alleviating and curing a wide range of pathologies, includingbut not limited to neurogical, psychiatric, cardiovascular,inflammatory, ophthalmic, urogenital, and gastrointestinal diseaseswhere the above mechanisms have been described as playing a pathologicalrole.

The compounds of this invention are substantially free from any MAOinhibitory effect or exhibit a significantly reduced MAO inhibitoryeffect at dosage that are therapeutically effective in preventing,alleviating and/or curing the above said affections.

BACKGROUND OF THE INVENTION Chemical Background

The patent application WO 90/14334 describes mono-substitutedN-phenylalkyl alpha-amino carboxamide derivatives of the followinggeneral formula

whereinR is a (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, furyl, thienyl, pyridyl or aphenyl ring optionally substituted by 1 to 4 substituents independentlyselected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and trifluoromethyl; Ais a —(CH₂)_(m)—, —(CH₂)_(p)—X—(CH₂)_(q)— group wherein m is an integerof 1 to 4, one of p and q is zero and the other is zero or an integer of1 to 4, X is —O—, —S— or —NR⁴— in which R⁴ is hydrogen or (C₁-C₄)alkyl;n is 0 or 1; each of R¹ and R² independently is hydrogen or(C₁-C₄)alkyl; R³ is hydrogen, (C₁-C₄)alkyl optionally substituted byhydroxy or phenyl optionally substituted as above; R^(3′) is hydrogen orR³ and R^(3′) taken together form a (C₃-C₆)cycloalkyl ring; each of R⁵and R⁶ independently is hydrogen or (C₁-C₆) alkyl; and their use asanti-epileptic, anti-Parkinson, neuroprotective, anti-depressant,anti-spastic and/or hypnotic agents.

The compound 2-[2-[4-(3-chlorobenzyloxy)-phenyl]-ethylamino]-acetamideand its hydrochloride salt and the preparation thereof are specificallydescribed in the above patent application. (See also P. Pevarello andal. in J. Med. Chem. 1998, 41, 579-590.)

The compounds (S)-2-[2-[4-benzyloxy-phenyl]-ethylamino]-acetamide,(S)-2-[2-[4-(2-cholorobenzyloxy)-phenyl]-ethylamino]-acetamide,2-[2-(4-benzyl-phenyl)-ethylamino]-acetamide and2-[2-(4-benzylamino-phenyl)-ethylamino]-acetamide are mentioned, but notcharacterized, in WO 90/14334.

The patent application WO 04/089353 describes a method and a combinationtherapy for the treatment of Parkinson' disease by using safinamide((S)-(+)-2-[4-(3-fluoro-benzyloxy)benzylamino]-propanamide), asafinamide derivative or a MAO-B inhibitor together withanti-Parkinsonian agents. The compound2-[2-[4-(3-chloro-benzyloxy)-phenyl]-ethylamino]-acetamide isexemplified in the invention.

The above compound is also prepared and described as anticonvulsivant(Pevarello P., Bonsignori A., Dostert P., Heidempergher F., PinciroliV., Colombo M., McArthur R. A., Salvati P., Post C., Fariello R. G.,Varasi M. J. Med. Chem. (1998) 41: 579-590).

The patent application WO 99/35125 describes alpha-aminoamidederivatives of the general formula

whereinR is a furyl, thienyl, pyridyl or a phenyl ring; A is a —(CH₂)_(m)—,—(CH₂)_(n)—X— or —(CH₂)_(n)—O— group wherein m is an integer of 1 to 4,n is zero or an integer of 1 to 4, X is —S— or —NH— and v is zero or aninteger of 1 to 5; s is 1 or 2; R¹ is hydrogen or (C₁-C₄)alkyl; one ofR² and R³ is hydrogen and the other is hydrogen or (C₁-C₄)alkyloptionally substituted by hydroxy or phenyl; or R² and R³ taken togetherform a (C₃-C₆)cycloalkyl ring; or R² and R³ are both methyl; R⁴ ishydrogen or C₁-C₄ alkyl; and their use as analgesic agents.

The compound2-[2-[4-(3-chloro-benzyloxy)-phenyl]-ethylamino]-propanamide in theabove patent application is mentioned.

The patent application WO 03/091219 describes5-(benzyloxy)-2-(iodophenyl)-ethylamino derivatives (see formula XII),which are employed as intermediates in the preparation of isoquinolinesas monoamine oxidase B inhibitors useful against Alzheimer's disease andsenile dementia:

wherein, inter alia, m is 1, 2, or 3; R² is selected from halogen,halogen —(C₁-C₆)alkyl, cyano, (C₁-C₆)alkoxy or halogen —C₁-C₆)alkoxy;R¹¹ is hydrogen; n is 0, 1 or 2; R⁴ and R⁵ are independently selectedfrom hydrogen, (C₁-C₆)alkyl, —(CH₂)_(p)—OR⁸, —(CH₂)_(p)—SR⁸ or benzyl,wherein p is 1 or 2 and R⁸ is hydrogen or (C₁-C₆)alkyl.

WO 99/26614 discloses substituted 2-(benzylamino)acetamides and theiruse for treating disorders responsive to the blockade of sodium ionchannels, including preventing or ameliorating neuropathic pain.

WO 03/037865 relates to compounds useful in the treatment of cancer ofgeneral formula

wherein the symbols R¹, R², R³ X, U and Y may assume a wide series ofmeanings. Although some combinations of said broad generic meaningsmight include phenethylamino derivatives, none of the compoundsdescribed in this application is actually disclosed in WO 03/037865.

U.S. Pat. No. 5,366,982 (WO 92/01675) relates to compounds havingselective leucotriene B₄ (LTB₄) antagonist properties, encompassed bythe general formula

wherein the symbols R, R′, R², R³, R⁴, X, Y, Z W, n, m and Q may assumea wide series of meanings. Notwithstanding some combinations of saidgeneric meanings might encompass also phenethylamino derivatives, noneof the compounds described in this application is actually disclosed inU.S. Pat. No. 5,366,982.WO 98/35957 discloses acetamide derivatives active as antagonists ofneuropeptide Y receptor, particularly useful in the treatment ofobesity, of general formula

where the symbols R¹, R², R³, R⁴ and R⁵ may assume a wide series ofmeanings. None of the compounds described in this application isactually disclosed in WO 98/35957.

EP 1588704A discloses alfa-aminoamide derivatives, including(S)-(+)-2-[4-(2-fluorobenzyloxy)-benzylamino]-propanamide, i.e.ralfinamide, for use in the treatment of Restless Leg Syndrome.

WO 2005/018627 discloses alfa-aminoamide derivatives, includingralfinamide, for use as therapeutic anti-inflammatory agents

Biological Background

Calcium channels are membrane-spanning, multi-subunit proteins thatallow controlled entry of calcium ions into cells from the extracellularfluid. Commonly, calcium channels are voltage dependent and are referredto as voltage-gated calcium channels (VGCC). VGCCs are found throughoutthe mammalian nervous system, where they regulate the intracellularcalcium ions levels that are important for cell viability and function.Intracellular calcium ion concentrations are implicated in a number ofvital processes in animals, such as neurotransmitter release, musclecontraction, pacemaker activity and secretion of hormones. All“excitable” cells in animals, such as neurons of the central nervoussystem (CNS), peripheral nerve cells, and muscle cells, including thoseof skeletal muscles, cardiac muscles and venous and arterial smoothmuscles, have voltage dependent calcium channels.

Calcium channels are a large family with many genetically,physiologically, and pharmacologically distinct subtypes. Based on thebiophysical properties of calcium currents recorded from individualneurons, two super-families have been described: High Voltage Activated(HVA) and Low Voltage Activated (LVA) calcium channels. Calcium currentsreferred as L-Type, P-Type, Q-Type, N-Type, R-Type are HVA and as T-Typeare LVA. In particular, the term “L-type” was originally applied tochannels with a large single channel conductance and long open time, and“T-type” was applied to channels with a tiny single channel conductanceand a transient open time. Further exploration of functional calciumchannel diversity identified the “N-type” channel expressed in neuronsand the “P-type” channel, which is the dominant type expressed incerebellar Purkinje neurons and is pharmacologically resistant to knownblockers of L-type and N-type calcium channels. From the molecularidentity, ten distinct calcium subtypes have been identified, cloned andexpressed and grouped in three families: Cav1 family (Cav 1.1, 1.2, 1.3,1.4) is functionally related to the L-type Ca current; Cav2 family (Cav2.1, 2.2, 2.3) is functionally related to the P/Q, N, R-type currentsand Cav3 (Cav 3.1, 3.2, 3.3) family is functionally related to theT-type current.

It is believed that calcium channels are relevant in certain diseasestates. A number of compounds useful in treating various cardiovasculardiseases in mammals, including humans, are thought to exert theirbeneficial effects by modulating functions of voltage dependent calciumchannels present in cardiac and/or vascular smooth muscle. Compoundswith activity against calcium channels have also been implicated for thetreatment of pain. In particular N-type calcium channels (Cav2.2),responsible for the regulation of neurotransmitter release, are thoughtto play a significant role in nociceptive transmission, both due totheir tissue distribution as well as from the results of severalpharmacological studies. N-type calcium channels were found up-regulatedin the ipsilateral dorsal horn in neuropathic pain models of injury(Cizkova D., Marsala J., Lukacova N., Marsala M., Jergova S., OrendacovaJ., Yaksh T. L. Exp. Brain Res. (2002) 147: 456-463). Specific N-typecalcium channel blockers were shown to be effective in reducing painresponses in neuropathic pain models (Mattews E. A., Dickenson A. H.Pain (2001) 92: 235-246), in the phase II of the formalin test (Diaz A.,Dickenson A. H. Pain (1997) 69: 93-100) and the hyperalgesia initiatedby knee joint inflammation (Nebe J., Vanegas H., Schaible H. G. Exp.Brain Res. (1998) 120: 61-69). Mutant mice, lacking the N-type calciumchannels, were found to have a decreased response to persistent pain asseen by a decrease in pain response during phase II of the formalin test(Kim C., Jun K., Lee T., Kim S. S., Mcenery M. W., Chin H., Kim H. L,Park J. M., Kim D. K., Jung S. J., Kim J., Shin H. S. Mol. Cell.Neurosci. (2001) 18: 235-245; Hatakeyama S., Wakamori M, Ino M.,Miyamoto N., Takahashi E., Yoshinaga T., Sawada K., Imoto K., Tanaka I.,Yoshizawa T., Nishizawa Y., Mori Y., Nidome T., Shoji S, Neuroreport(2001) 12: 2423-2427) as well as to neuropathic pain, assessed by adecrease in mechanical allodynia and thermal hyperalgesia in the spinalnerve ligation model. Interestingly, these mice also showed lower levelsof anxiety when compared to wild type (Saegusa H., Kurihara T., Zong S.,Kazuno A., Matsuda Y. Nonaka T., Han W., Toriyama H., Tanabe T., EMBO J.(2001) 20: 2349-2356). The involvement of N-type calcium channels inpain has been further validated in the clinic by ziconotide, a peptidederived from the venom of the marine snail, Conus Magnus. A limitationin the therapeutic use of this peptide is that it has to be administeredintrathecally in humans (Bowersox S. S, and Luther R. Toxicon, (1998)36: 1651-1658).

Sodium channels play an important role in the neuronal network bytransmitting electrical impulses rapidly throughout cells and cellnetworks, thereby coordinating higher processes ranging from locomotionto cognition. These channels are large transmembrane proteins, which areable to switch between different states to enable selective permeabilityfor sodium ions. For this process an action potential is needed todepolarize the membrane, and hence these channels are voltage-gated. Inthe past few years a much better understanding of sodium channels anddrugs interacting with them has been developed.

Voltage-gated sodium channels were originally classified based on theirsensitivity to tetrodotoxin, from low nanomolar (Tetrodotoxin sensitive,TTXs) to high micromolar (Tetrodotoxin resistant, TTXr). So far, 10different sodium channel α subunits have been identified and classifiedas Nav1.1 to Nav1.9. Nav1.1 to Nav1.4, Nav1.6 and Nav1.7 are TTXs,whereas Nav1.5, Nav1.8 and Nav.1.9 are TTXr, with different degrees ofsensitivity. Nav1.1 to Nav1.3 and Nav1.6, are primarily expressed in theCNS, whereas Nav1.4 and Nav1.5 are mainly expressed in muscle (skeletaland heart respectively) and Nav1.8 and Nav1.9 are predominantlyexpressed in small DRGs.

It has become clear that a number of drugs having an unknown mechanismof action actually act by modulating sodium channel conductance,including local anaesthetics, class I antiarrhythmics andanticonvulsants. Neuronal sodium channel blockers have found applicationwith their use in the treatment of epilepsy (phenyloin andcarbamazepine), bipolar disorder (lamotrigine), preventingneurodegeneration, and in reducing neuropathic pain. Variousanti-epileptic drugs that stabilize neuronal excitability are effectivein neuropathic pain (gabapentin, carbamazepine).

In addition, an increase in sodium channel expression or activity hasalso been observed in several models of inflammatory pain, suggesting arole of sodium channels in inflammatory pain.

All together these findings indicate that compounds with sodium and/orcalcium channel blockade have a high therapeutic potential inpreventing, alleviating and curing a wide range of pathologies,including neurological, psychiatric, cardiovascular, urogenital andgastrointestinal diseases, where the above mechanisms have beendescribed as playing a pathological role.

There are many papers and patents which describe sodium channel and/orcalcium channel modulators or antagonists for the treatment ormodulation of a plethora of disorders, such as their use as localanaesthetics, antiarrhythmics, antiemetics, antimanic anti-depressants,agents for the treatment of unipolar depression, cardiovasculardiseases, urinary incontinence, diarrhoea, inflammation, epilepsy,neurodegenerative conditions, nerve cell death, neuropathic pain,migraine, acute hyperalgesia and inflammation, renal disease, allergy,asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, urinarytract disorders, gastrointestinal motility disorders, premature labour,obesity.

A non-exhaustive list of such papers and patents/patent applicationsdescribing sodium and/or calcium channels blockers and uses thereofincludes the references shown below.

C. Alzheimer describes in Adv. Exp. Med. Biol. 2002, 513, 161-181,sodium and calcium channels as targets of neuroprotective substances.

Vanegas e Schaible (Pain 2000, 85, 9-18) discuss effects of antagonistsof calcium channels upon spinal mechanisms of pain, hyperalgesia andallodynia.

U.S. Pat. No. 5,051,403 relates to a method of reducing neuronal damageassociated with an ischemic condition, such as stroke, by administrationof binding/inhibitory omega-conotoxin peptide wherein the peptide ischaracterized by specific inhibition of voltage-gated calcium channelcurrents selectively in neuronal tissues.

U.S. Pat. No. 5,587,454 relates to compositions and methods of producinganalgesia particularly in the treatment of pain and neuropathic pain.

U.S. Pat. No. 5,863,952 relates to calcium channel antagonists for thetreatment of ischaemic stroke.

U.S. Pat. No. 6,011,035 relates to calcium channel blockers, useful inthe treatment of conditions such as stroke and pain.

U.S. Pat. No. 6,117,841 relates to calcium channel blockers and theiruse in the treatment of stroke, cerebral ischemia, pain, head trauma orepilepsy.

U.S. Pat. No. 6,362,174 relates to N-type calcium channel blockers inthe treatment of stroke, cerebral ischemia, pain, epilepsy, and headtrauma.

U.S. Pat. No. 6,380,198 concerns the use of the calcium channel blockerflunarizine for the topical treatment of glaucoma.

U.S. Pat. No. 6,420,383 and U.S. Pat. No. 6,472,530 relate to novelcalcium channel blockers, useful for treating and preventing a number ofdisorders such as hypersensitivity, allergy, asthma, bronchospasm,dysmenorrhea, esophageal spasm, glaucoma, premature labor, urinary tractdisorders, gastrointestinal motility disorders and cardiovasculardisorders.

U.S. Pat. No. 6,458,781 relates to compounds that act to block calciumchannels and their use to treat stroke, cerebral ischemia, pain, headtrauma or epilepsy.

U.S. Pat. No. 6,521,647 relates to the use of calcium channel blockersin the treatment of renal disease in animals, especially chronic renalfailure.

WO 97/10210 relates to tricyclic heterocyclic derivatives, and their usein therapy, in particular as calcium channel antagonists, e.g. for thetreatment of ischaemia, in particular ischaemic stroke.

WO 03/018561 relates to quinoline compounds as N-type calcium channelantagonists and methods of using such compounds for the treatment orprevention of pain or nociception.

WO 03/057219 relates to sodium channel blockers useful as agents fortreating or modulating a central nervous system disorder, such asneuropathic pain, inflammatory pain, inflammation-related pain orepilepsy.

WO99/14199 discloses substituted1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines-10-oles as potentsodium channel blockers useful for the treatment of several diseases,such as stroke, neurodegenerative disorders, Alzheimer's Disease,Parkinson's Disease and cardiovascular disorders.

WO01/74779 discloses new aminopyridine sodium channel blockers and theiruse as anticonvulsants, local anesthetics, as antiarrythmics, for thetreatment or prevention of neurodegenerative conditions, such asamyotrophic lateral sclerosis (ALS), for the treatment or prevention ofboth, acute or chronic pain, and for the treatment or prevention ofdiabetic neuropathy.

WO04/087125 discloses amino acid derivatives as inhibitors of mammaliansodium channels, useful in the treatment of chronic and acute pain,tinnitus, bowel disorders, bladder dysfunction and demyelinatingdiseases.

Monoamine oxidase (MAO) is an enzyme present in the outer mitochondrialmembrane of neuronal and non-neuronal cells. Two isoforms of MAO exist:MAO-A and MAO-B. MAO enzymes are responsible for the oxidativedeamination of endogenous and xenobiotic amines, and have a differentsubstrate preference, inhibitor specificity, and tissue distribution.For MAO-A serotonin, noradrenaline and adrenaline are preferentialsubstrates, and clorgyline is a selective MAO-A inhibitor; whereas MAO-Bprefers β-phenylethylamine as a substrate, and is almost selectivelyinhibited by selegiline. Dopamine, tyramine and tryptamine are oxidizedby both MAO-A and MAO-B, in particular in human brain dopamine isdeaminated by 80% by MAO-B.

MAO inhibition allows endogenous and exogenous substrates to accumulateand may thereby, when almost fully inhibited (>90%), alter the dynamicsof regular monoamine transmitters. MAO regulate the concentrations inthe brain of the most important neurotransmitters such as noradrenaline,serotonin and dopamine which are related to emotion, anxiety andmovement. Thus, it is thought that MAO be closely linked to variouspsychiatric and neurological disorders such as depression, anxiety andParkinson's disease (PD).

MAO-A inhibitors are mainly used in psychiatry for the treatment ofmajor, refractory and atypical depression as a consequence of theirability to increase the reduced serotonin and noradrenalin brain levels.More recently, MAO-A inhibitors have been used to treat patients withanxiety disorders such as social phobia, panic disorders, post-traumaticstress disorders and obsessive compulsive disorders.

MAO-B inhibitors are mainly used in neurology for the treatment of PD.

There is also recent evidence and interest in the role of MAO-B in otherpathological conditions such as Alzheimer disease (AD). So far noevidence have been reported on MAO-B involvement in the metabolism ofco-transmitters, such as colecystokinin, substance P, somatostatin andneurotensin, which are involved in the modulation of pain sensation. Forthis reason there is no scientific rationale for the use of MAO-Binhibitors in pain syndromes. Adverse drug reactions during clinicalpractice with MAO inhibitors have been reported. First generation ofnon-selective and irreversible MAO inhibitors, such as tranylcypromideand phenelzine, have serious side effects, including hepatotoxicity,orthostatic hypotension and most importantly hypertensive crisis thatoccurs following the ingestion of foods containing tyramine (Cooper AJ.-Tyramine and irreversible monoamine oxidase inhibitors in clinicalpratice.—Br J Psych Suppl 1989:38-45).

When these non-selective and irreversible MAO inhibitors are used, astrict tyramine-reduced diet must be observed. The pressor sensitivitytowards tyramine is normalized 4 weeks after cessation oftranylcypromine therapy and more than 11 weeks after cessation ofphenelzine therapy.

Selegiline, a almost selective and irreversible MAO-B inhibitor,especially when used in combination with levodopa, can causeanorexia/nausea, dry mouth, dyskinesia and orthostatic hypotension inpatients with PD, the latter being most problematic (Volz H. P. andGleiter C. H.—Monoamine oxidase inhibitors. A perspective on their usein the elderly.—Drugs Aging 13 (1998), pp. 341-355).

In monotherapy, anorexia/nausea, musculoskeletal injuries, and cardiacarrhytmias occurred more often in patients receiving selegiline comparedwith those receiving placebo. Apart from these adverse effects,increased rates of elevated serum AST and ALT levels were noted.

The most frequently reported adverse effect of moclobemide, a selectiveand reversible MAO-A inhibitor, are sleep disturbances, increasedanxiety, restlessness, and headache.

The combination of selective serotonin reuptake inhibitors (SSRIs) andmoclobemide has good efficacy in cases of refractory depression, but hascreated controversy as to whether toxic side effects, such asserotonergic syndrome, result from this combination (BaumannP.—Pharmacokinetic-pharmacodynamic relationship of the selectiveserotonin reuptake inhibitors. Clin Pharmacokinet 31 (1996), pp444-469). Because of cardiac arrhythmias and increased liver enzymelevels, electrocardiogram and laboratory values should be checkedregularly.

Many types of physiologic changes that occur with aging affect thepharmacodynamics and pharmacokinetics of MAO inhibitors. Indeed,pharmacokinetic variables in the elderly are markedly different formthose in younger patients. These variables including absorption,distribution, metabolism and excretion have to be taken into account toavoid or minimize certain adverse effects and drug-drug interactions.Elderly patients are generally more susceptible than younger patients toside effects, including adverse drug reactions. Hypertensive crisis mayoccur more frequently in elderly than in younger patients, becausecardiovascular systems of the elderly are already compromised by age.

The use of sympathomimetic drugs in combination with MAO inhibitors mayalso elevate blood pressure. In addition, compared with placebo,phenelzine was associated with a significantly higher incidence ofdrowsiness, tremor, dyskinesia, diarrhea, micturition difficulties,orthostatic effects, and adverse dermatological effects. It isinteresting to note that in the elderly, headache is reported with ahigher frequency than in younger patients during treatment withmoclobemide (Volz H. P. and Gleiter C. H.—Monoamine oxidase inhibitors.A perspective on their use in the elderly. Drugs Aging 13 (1998), pp.341-355).

MAO inhibitors are sometimes prescribed for depression. Because of thepotential risk of suicide, adverse drug reactions and toxicity due tooverdose are important factors to consider when choosing anantidepressant. In addition, when MAO inhibitors are used in highdosage, adverse cardiovascular effects seem to increase considerably;and because MAO selectivity is lost with such high doses, tyramine caninduce potentially dangerous hypertensive reactions. Acute overdose withMAO inhibitors causes agitation, hallucinations, hyperpyrexia,hyperreflexia and convulsions. Abnormal blood pressure is also a toxicsign, so that gastric lavage and maintenance of cardiopulmonary functionmay be required. Overdose of traditional non-selective and irreversibleMAO inhibitors are considerably dangerous and sometimes fatal (Yamadaand Richelson, 1996. Pharmacology of antidepressants in the elderly. In:David J R, Snyder L., editors. Handbook of pharmacology of aging. BocaRaton: CRC Press 1996).

In the treatment of the affections wherein sodium and calcium channelsmechanism(s) play(s) a pathological role and, in particular, of painsyndromes (either of neuropathic or inflammatory type) inhibition of MAOenzymes is of no benefits. The most clinically active anti-nociceptivedrugs are devoid of MAO inhibition. On the contrary, MAO inhibitory sideeffects may impose at least two types of negative limitations.

1) Dietary: eating food with high tyramine content may cause severe,even life threatening increase of systemic blood pressure (the so called“cheese-effect”).

2) Pharmacological: pain is often treated with a combination of drugssuch as opioid derivatives and tricyclic antidepressant. With MAOinhibitors such association is dangerous as it may cause theserotoninergic syndrome (agitation, tremors, hallucination, hyperthermiaand arrhythmias).

Thus, eliminating or significantly reducing MAO inhibitory activity inmedicaments active as sodium and/or calcium channel modulators useful inpreventing, alleviating and curing a wide range of pathologies wheresaid mechanism(s) play(s) a pathological role, including neurological,psychiatric, cardiovascular, inflammatory, ophtalmic, urogenital andgastrointestinal diseases, is an unexpected and substantial therapeuticimprovement versus compounds of similar efficacy but with the abovementioned side effects. Said improvement is particularly desirable forthe medicaments active as sodium and/or calcium channel modulatorsuseful, in particular, for the treatment of the pain syndromes.

Taken into account these findings on MAO inhibitors and, in particular,lacking any evidence on MAO-B role in pathological affections like pain,migraine, cardiovascular, inflammatory, urogenital and gastrointestinaldiseases, it might be conceivable that MAO-B inhibition should not be anessential feature for compounds indicated for the above pathologies,avoiding any possible side effects during chronic and/or long-termtreatments.

An advantageous solution to the above described problem would consist inproviding medicaments which are “selectively active as sodium and/orcalcium modulators” or a useful for the “selective treatment” ofaffections disorders or diseases wherein the sodium and/or calciumchannel mechanism(s) play(s) a pathological role. With this expressionare intended medicaments which, when administered to a patient in needthereof in amounts that are effective in the treatment of the above saidaffections wherein the above said mechanism(s) play(s) pathologicalrole, do not exhibit any MAO inhibitory activity or exhibit asignificantly reduced MAO inhibitory activity, thus resulting inavoidance of side effects due to accumulation of endogenous andexogenous monoamine transmitters.

It is a primary object of this invention the use of phenylethylaminoderivatives for the manufacture of medicaments active as sodium and/orcalcium channel modulators for the treatment of pathologies where theabove said mechanism(s) play(s) a pathological role, said medicamentsbeing substantially free from any MAO inhibitory activity or havingsignificantly reduced MAO inhibitory activity and, therefore, having areduced potential for unwanted side effects. Said use provides animproved selective resource for the prevention, alleviation and/or cureof the above said pathological affections.

DESCRIPTION OF THE INVENTION

We have now found a new class of phenylethylamino derivatives highlypotent as sodium and/or calcium channel modulators and substantiallyfree from any MAO inhibitory activity or having significantly reducedMAO inhibitory activity and, thus, having potentially reduced sideeffects in preventing, alleviating and curing a wide range ofpathologies, including but not limited to neurogical, psychiatric,cardiovascular, inflammatory, ophthalmic, urogenital andgastrointestinal diseases where the above mechanisms have been describedas playing a pathological role.

In this description and claims, the expression “sodium and/or calciumchannel modulator(s)” means compounds able to block sodium and/orcalcium currents in a voltage dependent manner.

Therefore, object of the present invention is a compound of generalformula I

wherein:(a)

-   J is a group A-[(CH₂)_(n)—O]_(r)— in para position with respect to    the ethylamino chain wherein:    -   n is zero or 1; and    -   r is 1;    -   A is trifluomethyl; cyclopentyl; or phenyl optionally        substituted with a halo group;-   W is (C₁-C₄)alkoxy;-   R is hydrogen;-   R⁰ is hydrogen; or (C₁-C₂)alkyl;-   R¹ is hydrogen; (C₁-C₄)alkyl optionally substituted with a hydroxy    group; cyclopropylmethyl; 2-propyn-1-yl; benzyl optionally    substituted with one or two (C₁-C₂)alkoxy groups on the benzene    ring; thiazolyl; a 5-6 membered saturated heterocyclyl containing a    nitrogen atom, optionally substituted with a (C₁-C₂)alkyl group; or    heterocyclylmethyl wherein the heterocyclyl group is a 5-6 membered    heterocylyl containing 1 to 3 hetero atoms selected from nitrogen,    oxygen and sulfur, optionally substituted with one or two groups    selected from (C₁-C₂)alkyl, hydroxymethyl and (C₁-C₂)alkoxy;-   R² is hydrogen; (C₁-C₄)alkyl; or phenyl;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; (C₁-C₄)alkyl optionally substituted with a group    selected from amino, (C₁-C₄)alkylamino, di-(C₁-C₄)alkylamino,    imidazolyl and pyrrolidinyl wherein the imidazolyl and the    pyrrolidinyl group is optionally substituted with a (C₁-C₂)alkyl    group; or benzyl; or-   R³ and R⁴, taken together with the adjacent nitrogen atom, form a    pyrrolidinyl, morpholinyl or piperazinyl ring optionally substituted    with a (C₁-C₂)alkyl group; or    (b)-   J is a group A-[(CH₂)_(n)—O]_(r)— in para position with respect to    the ethylamino chain wherein:    -   n is 1; and    -   r is 1;    -   A is phenyl; or phenyl substituted with a halo group;-   W is hydrogen;-   R is hydrogen;-   R⁰ is (C₁-C₂)alkyl;-   R¹ is hydrogen;-   R² is (C₁-C₂)alkyl;-   R³ is hydrogen; or (C₁-C₄) alkyl; and-   R⁴ is hydrogen; or (C₁-C₄)alkyl; or    (c)-   J is hydrogen;-   W is a group A-[(CH₂)_(n)—O]_(r)— wherein:    -   n is zero, 1 or 2; and    -   r is zero or 1;    -   A is (C₁-C₄)alkyl, trifluoromethyl; cyclopropyl; cyclopentyl;        phenyl optionally substituted with a group selected from halo,        methyl, methoxy, trifluoromethyl, acetylamino, and        dimethylaminomethyl; thienyl optionally substituted with a        chloro group; furanyl; isoxazolyl optionally substituted with        one or two methyl groups; piperidinyl; morpholinyl; pyridinyl or        pyrimidinyl, the pyridinyl and pyrimidinyl ring being optionally        substituted with one or two methoxy groups;-   R is hydrogen; or fluoro;-   R⁰ is hydrogen; or (C₁-C₂)alkyl;-   R¹ is isopropyl; cyclopropylmethyl; furanylmethyl;    tetrahydrofuranyl; or tetrahydrofuranylmethyl;-   R² is hydrogen; or (C₁-C₄)alkyl;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; (C₁-C₄)alkyl optionally substituted with a group    selected from (C₁-C₂)alkoxy, amino, (C₁-C₄)alkylamino and    di-(C₁-C₄)alkylamino; or heterocyclyl wherein the heterocyclyl is    selected from isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and 1,3,4    thiadiazolyl and may be optionally substituted with a (C₁-C₂)alkyl    group; or-   R³ and R⁴ taken together with the adjacent nitrogen atom form a    pyrrolidine ring;    with the proviso that when A is (C₁-C₄)alkyl, trifluoromethyl,    cyclopropyl or cyclopentyl, then r is 1; and with the further    proviso that when R¹ is isopropryl, then A is trifluoromethyl and n    is 1;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts.

The term “(C₁-C₄)alkyl” or the “(C₁-C₄) alkyl” moiety in the othersubstitutents (e.g. in the terms alkoxy, mono and di-alkylamino) as usedin this description and claims, when no otherwise specified, identifiesa straight or branched alkyl radical or moiety; examples of saidradicals or moieties include, respectively: methyl, ethyl, propyl,isopropyl, butyl, isobutyl and tert-butyl or methoxy, ethoxy, propoxy,isopropoxy, butoxy isobutoxy and tert-butoxy.

The term “halo”, when no otherwise specified herein, means an halogenatom radical such as fluoro, chloro, bromo and iodo.

The term “heterocycle” and “heterocyclyl” when not otherwise specifiedherein, identifies a wholly unsaturated, a partially unsaturated or asaturated monocyclic 5 or 6 membered heterocyclic containing from 1 to 3hetero atoms selected from nitrogen, oxygen and sulfur.

Examples of a monocyclic 5 or 6 membered wholly unsaturated heterocyclecontaining from 1 to 3 heteroatoms selected from nitrogen, oxygen andsulphur comprise, for instance, pyrrole, furan, thiophene, pyrazole,imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3 and 1,3,4thiadiazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, andtriazine. Examples of a monocyclic 5-6 membered partially unsaturatedheterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygenand sulfur comprise, for instance, pyrroline, pyrazoline, imidazoline,oxazoline, isoxazolidine and thiazoline.

Examples of a monocyclic 5 or 6 membered saturated heterocyclecontaining from 1 to 3 heteroatoms selected among nitrogen, oxygen andsulphur comprise, for instance, pyrrolidine, pyrazolidine,imidazolidine, oxazolidine, isoxazolidine, piperidine, piperazine,tetrahydrofuran, tetrahydropyran, morpholine and thiomorpholine.

Where the compounds of this invention contain at least one asymmetriccarbon atom they can exist as single enantiomers or diastereoisomers ora mixture thereof, the invention includes within its scope all thepossible single enantiomers or diastereoisomers of said compounds andthe mixtures thereof, e.g., the racemic mixtures.

Examples of pharmaceutically acceptable salts of the compounds offormula I are salts with organic and inorganic acids such ashydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric,acetic, propionic, tartaric, fumaric, citric, benzoic, succinic,cinnamic, mandelic, salicylic, glycolic, lactic, oxalic, malic, maleic,malonic, fumaric, tartaric, p-toluenesulfonic, methanesulfonic, glutaricacid and the like.

The compounds of formula I are active as calcium and/or sodium channelmodulators and therefore useful in preventing alleviating and curing awide range of pathologies, including but not limited to neurological,psychiatric, cardiovascular, inflammatory, ophthalmic, urologic andgastrointestinal diseases where the above mechanisms have been describedas playing a pathological role.

A preferred group of compounds of formula I of this invention comprisesa compound of group (a) defined above wherein:

-   J is a group A-[(CH₂)_(n)—O]_(r)— in para position with respect to    the ethylamino chain wherein:    -   n is 1; and    -   r is 1;    -   A is trifluoromethyl; cyclopentyl; phenyl; or phenyl substituted        with a fluoro or chloro group;-   W is methoxy;-   R is hydrogen;-   R⁰ is hydrogen;-   R¹ is hydrogen; (C₁-C₄)alkyl; hydroxyethyl; cyclopropylmethyl;    2-propin-1-yl; benzyl optionally substituted with one or two methoxy    groups on the benzene ring; piperidinyl optionally substituted with    a methyl group; thiazolyl; or heterocyclylmethyl wherein the    heterocyclyl group is selected from isoxazolyl optionally    substituted with a methyl or methoxy group, imidazolyl optionally    substituted with a methyl group, furanyl optionally substituted with    a hydroxymethyl group, tetrahydrofuranyl, 1,2,3-thiadiazolyl,    pyrazolyl optionally substituted with one or two methyl groups,    pyridinyl optionally substituted with a methoxy group, thienyl and    thiazolyl;-   R² is hydrogen; (C₁-C₄)alkyl; or phenyl;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; (C₁-C₄)alkyl optionally substituted with a group    selected from amino, dimethylamino, imidazolyl and pyrrolidinyl    wherein the pyrrolidinyl is optionally substituted with a methyl    group; or benzyl; or-   R³ and R⁴ taken together with the adjacent nitrogen atom form a    pyrrolidinyl, piperazinyl or morpholinyl ring optionally substituted    with a methyl group;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts.

A further group of preferred compounds of formula I of this inventioncomprises a compound of group (b) defined above wherein:

-   J is a group A-[(CH₂)_(n)—O]_(r)— in para position with respect to    the ethylamino chain wherein:    -   n is 1; and-   r is 1;-   A is phenyl; or phenyl substituted with a fluoro or chloro group;-   W is hydrogen;-   R is hydrogen;-   R⁰ is methyl;-   R¹ is hydrogen;-   R² is methyl;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; or (C₁-C₄)alkyl;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts.

A further group of preferred compounds of formula I of this inventioncomprises those compounds of group (c) defined above wherein:

-   J is hydrogen;-   W is a group A-[(CH₂)_(n)—O—]_(r)— wherein:    -   n is zero, 1 or 2;    -   r is zero or 1;    -   A is (C₁-C₄)alkyl; trifluoromethyl; cyclopropyl; cyclopentyl;        phenyl optionally substituted with a group selected from fluoro,        chloro, methyl, methoxy, trifluoromethyl, acetylamino and        dimethylaminomethyl; thienyl optionally substituted with a        chloro group; furanyl; isoxazolyl optionally substituted with        one or two methyl groups; piperidinyl; morpholinyl; pyridinyl or        pyrimidinyl, the pyridinyl and pyrimidinyl group being        optionally substituted with one or two methoxy groups;-   R is hydrogen; or fluoro;-   R⁰ is hydrogen;-   R¹ is cyclopropylmethyl; furanylmethyl; tetrahydrofuranyl; or    tetrahydrofuranylmethyl;-   R² is hydrogen; or methyl;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; (C₁-C₄)alkyl optionally substituted with a group    selected from methoxy, amino, methylamino and dimethylamino;    isoxazolyl optionally substituted with a methyl group; pyrazolyl;    imidazolyl; thiazolyl; or 1,3,4 thiazolyl; or-   R³ and R⁴ taken together with the adjacent nitrogen atom form a    pyrrolidine ring;    with the proviso that when A is (C₁-C₄)alkyl, trifluoromethyl,    cyclopropyl or cyclopentyl, then r is 1;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts.

A more preferred group of compounds of formula I encompassed by group(c) defined above comprises a compound wherein;

-   J is hydrogen;-   W is a group A-[(CH₂)]_(n)—O]_(r)— wherein:    -   n is 1 or 2;    -   r is 1;    -   A is (C₁-C₄)alkyl; trifluoromethyl; cyclopropyl; cyclopentyl;        phenyl optionally substituted with a group selected from fluoro,        chloro, methyl, methoxy, and trifluoromethyl; thienyl optionally        substituted with a chloro group; isoxazolyl optionally        substituted with one or two methyl groups; pyridinyl;        piperidinyl; or morpholinyl;-   R is hydrogen; or fluoro;-   R⁰ is hydrogen;-   R¹ is cyclopropylmethyl; furanylmethyl; tetrahydrofuranyl; or    tetrahydrofuranylmethyl;-   R² is hydrogen;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; (C₁-C₄)alkyl optionally substituted with a group    selected from methoxy, amino, methylamino and dimethylamino;    isoxazolyl optionally substituted with a methyl group; pyrazolyl;    imidazolyl; thiazolyl; or 1,3,4 thiazolyl; or-   R³ and R⁴ taken together with the adjacent nitrogen atom form a    pyrrolidine ring;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts.

Among this group of more preferred compounds of formula I of the group(c) herein above defined a most preferred group of compounds comprises acompound wherein:

-   J is hydrogen;-   W is a group A-[(CH₂)_(n)—O]_(r)— wherein:    -   n is 1;    -   r is 1;    -   A is (C₁-C₄)alkyl;-   R is hydrogen;-   R⁰ is hydrogen;-   R¹ is furanylmethyl; or tetrahydrofuranylmethyl;-   R² is hydrogen;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is (C₁-C₄)alkyl;    either as a single enantiomer or, if the case, diastereoisomer, or    mixture thereof and its pharmaceutically acceptable salts.

A further more preferred group of compounds of formula I encompassed bythe group (c) defined above comprises a compound wherein:

-   J is hydrogen;-   W is a group A-[(CH₂)_(n)—O]_(r)— wherein:    -   n is zero;    -   r is 1;-   A is cyclopentyl; or phenyl optionally substituted with a fluoro    group;-   R is hydrogen;-   R¹ is furanylmethyl;-   R² is hydrogen;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; or (C₁-C₄)alkyl;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts.

A further more preferred group of compounds of formula I encompassed bythe group (c) defined above comprises a compound wherein:

-   J is hydrogen;-   W is a group A-[(CH₂)_(n)—O]_(r)— wherein:    -   n is zero;    -   r is zero;    -   A is phenyl optionally substituted with a group selected from        fluoro, methoxy, acetylamino and dimethylaminomethyl; thienyl;        furanyl; isoxazolyl optionally substituted with one or two        methyl groups; piperidinyl; pyridinyl or pyrimidinyl, the        pyridinyl and pyrimidinyl group being optionally substituted        with one or two methoxy groups;-   R is hydrogen;-   R⁰ is hydrogen;-   R¹ is furanylmethyl; or tetrahydrofuranylmethyl;-   R² is hydrogen;-   R³ is hydrogen; or (C₁-C₄)alkyl; and-   R⁴ is hydrogen; or (C₁-C₄)alkyl;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts.

Most preferably, a compound of formula I according to this invention isselected from the group consisting of:

-   2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-acetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-isobutylamino]-N-methyl-acetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N-methyl-acetamide;-   2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-acetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N,N-dimethyl-acetamide;-   2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-propionamide;-   2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-2-phenyl-acetamide;-   2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1-(morpholin-4-yl)-2-phenyl-ethanone;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-acetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-1-(pyrrolidin-1-yl)ethanone;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-amino-2-methylpropyl)-acetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-dimethylaminoethyl)-acetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-acetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-ethylacetamide;-   2-[[2-[4-(Benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methylacetamide;-   2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide;-   2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide;-   2-[[2-[3-(2-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide;-   2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-acetamide;-   2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-dimethylaminoethyl)-acetamide;-   2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-amino-2-methylpropyl)-acetamide;-   2-[[2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-isopropylamino]-N,N-dimethyl-acetamide;-   2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-propionamide;-   2-[[2-[3-Methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide;-   2-[[2-(3′-Fluoro-biphenyl-3-yl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide;-   2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;-   2-[[2-[(3-Butoxy-phenyl)]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;-   2-[[2-(3-Butoxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide    hydrochloride-   2-[[2-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;-   2-[[2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide;-   2-[[2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide;-   2-[[2-(3-Piperidin-1-yl-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;-   (2S)-2-[2-(4-Benzyloxy)-phenyl]-1-methyl-ethylamino]-propionamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide;-   (S)-2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-4-methyl-valeramide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(furan-3-ylmethyl)amino]-N-methylacetamide;-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-ethyl-acetamide;    and-   2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(6-methoxy-pyridin-3-ylmethyl)amino]-N-methyl-acetamide;    if the case, either as a single enantiomer or diastereoisomer or    mixture thereof and its pharmaceutically acceptable salts,    preferably its salt with hydrochloric acid.

The compounds of formula I, object of the present invention, areprepared according to a synthetic process which comprises:

a) the reaction of a compound of formula II

whereinJ, W, R, R⁰, and R¹, have the same meanings defined in formula I above,with a compound of formula III

whereinR², R³ and R⁴ have the same meanings as defined in formula I above and Zis a halogen atom or a good leaving group such as, for example,methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonategroups; orsaid reaction is alternatively carried out between a compound of formulaII and a compound of formula IV

whereinR² and Z have the meanings defined above and R⁵ is a (C₁-C₄)alkyl group,to give a compound of formula V

whereinJ, W, R, R⁰, R¹, R², and R⁵, and have the same meanings as definedabove; which is further reacted with an amine of formula HNR³R⁴ where R³and R⁴ are as defined above, to give the compounds of the invention.

The amidation reaction which allows the introduction of the substituent—NR³R⁴ is carried out according to conventional amidation techniqueswhereby an ester is converted to the corresponding amide by reactionwith the selected amine. According to a practical embodiment of theinvention the amidation is carried out in the presence oftrimethylaluminium.

The compound of formula I wherein J, W, R, R⁰, R², R³, and R⁴ have thesame meanings as above and R¹ has the same meanings as above, apart fromhydrogen, can be prepared also through the reaction of a compound offormula VI

whereinJ, W, R, R⁰, R², R³, and R⁴, have the same meanings as in formula Iabove, with a compound R¹-Z, wherein R¹ has the meanings reported aboveapart from hydrogen and Z is a halogen atom or a good leaving group,e.g. methanesulfonyloxy, p-toluenesulfonyloxy ortrifluoromethanesulfonyloxy in the presence of a base or with a carbonylcompound of the formula R⁶R⁷CO in the presence of a reducing agent,wherein R⁶ is: hydrogen; a (C₁-C₃)alkyl optionally substituted with ahydroxy group; cyclopropyl; ethynyl; phenyl optionally substituted withone or two (C₁-C₂)alkoxy groups; a 5 or 6 membered heterocyclylcontaining from 1 to 3 heteroatoms selected from nitrogen, oxygen andsulphur, where the heterocyclyl is optionally substituted with one ortwo groups selected from (C₁-C₂)alkyl, hydroxymethyl and (C₁-C₂)alkoxy;R⁷ is hydrogen; or R⁶ and R⁷ taken together with the adjacent carbonylgroup represent a (C₃-C₄)aliphatic, ketone or a 5-6 membered saturatedheterocyclic ketone containing a nitrogen or a oxygen atom optionallysubstituted with a (C₁-C₂)alkyl group, e.g. 1-methyl-piperidin-4-one ordihydrofuran-3(2H)-one.

A compound of the invention may be converted into another compound ofthe invention. For instance, a compound of formula I wherein Jrepresents a benzyloxy radical may be transformed into the correspondinghydroxy-derivative by catalytic hydrogenation and then reacted with anappropriate reagent to replace the original benzyl moiety with adifferent group, e.g., a trifluoromethylbenzyl, phenylethyl,trifluoroethyl, cyclopentyl, cyclopropylmethyl and heterocyclylmethylgroup as defined above. If desired, a compound of the invention may beconverted into a pharmaceutically acceptable salt and/or, if desired, asalt may be converted into a free compound and/or, if desired, a mixtureof enantiomers or diastereoisomers of compounds of the invention may beseparated into the corresponding single isomers.

The compounds of formula II, III, IV and VI are commercially availableor are prepared from commercially available compounds according towell-known methods.

According to a practical embodiment of the invention the preparation ofa compound of formula II is carried out by reacting a compound offormula VII

whereinJ, W, and R, have the meanings defined in formula I, with a nitroalkaneof the formula R⁰—CH₂—NO₂ wherein R⁰ has the same meanings defined informula I to give a compound of formula VIII

whereinJ, W, R, and R⁰ have the same meanings as in formula I, which is reducedwith a reducing agent such as LiAlH₄ or by catalytic reduction usingPt/H₂ or Pd/H₂ to give a compound of formula II wherein R¹ is hydrogen.

When it is desired a compound of formula II wherein R¹ has the samemeanings as above apart from hydrogen, the compound of formula IIwherein R¹ is hydrogen is reacted with a compound of formula R¹Z whereinR¹ has the same meanings as above apart from hydrogen, in the presenceof a base, or with a carbonyl compound of formula R⁶R⁷CO wherein R⁶ andR⁷ have the same meanings as defined above, in the presence of areducing agent.

The reaction between a compound of formula II and a compound of formulaIII to give a compound of the invention is carried out according toknown methods.

According to a preferred embodiment of the invention said reaction iscarried out in the presence of a base and, more preferably, said base isselected from K₂CO₃, triethylamine or diisopropylethylamine.

When a compound of formula I is obtained wherein R¹ is hydrogen (i.e., acompound of formula VI) the introduction of a radical R¹ which is otherthan hydrogen defined above is carried out according to conventionalmethods for the preparation of secondary or tertiary amines such asalkylation or reductive amination techniques.

According to a preferred embodiment of the invention said alkylationreaction is carried out in the presence of a base and, more preferably,said base is selected from K₂CO₃, triethylamine anddiisopropylethylamine.

According to another preferred embodiment of the invention saidreductive amination with a compound R⁶R⁷CO, wherein R⁶ and R⁷ have thesame meanings as defined above is carried out in the presence of areducing agent selected from NaBH₄, NaBH₃CN and(polystyrylmethyl)trimethylammonium cyanoborohydride.

As an alternative method, the compounds of formula I are preparedaccording to a synthetic process which comprises the reaction of acompound of formula IX

whereinJ, W, R, and R⁰ have the same meanings as defined in formula I, or acompound of formula X

whereinJ, W, R, and R⁰ have the same meanings as defined in formula I and Z isas defined above; with a compound of formula XI

whereinR¹, R², R³ and R⁴ have the meanings defined in formula I in the presenceof a reducing agent in the case of the reaction of IX with XI or a basein the case of the reaction between X and XI.

The reaction between a compound of formula IX and a compound of formulaXI to give a compound of the invention is a reductive amination and thereaction of a compound of formula X with a compound of formula XI is analkylation reaction: these reactions are carried out according toconventional techniques.

Preferred reducing agents used in the reaction between the compound offormula IX and XI are selected from NaBH₄, NaBH₃CN and(polystyrylmethyl)-trimethylammonium cyanoborohydride.

According to a preferred embodiment of the invention the reactionbetween the compound of formula X and XI is carried out in the presenceof a base and, more preferably, said base is selected from K₂CO₃,triethylamine or diisopropylethylamine.

In the preparation of the compounds of formula I and the startingmaterials and/or intermediates described herein it may be useful toprotect certain groups which are sensitive to the reaction conditions.

The evaluation of the usefullness of the optional protection, as well asthe selection of the suitable protecting agent, according to thereaction carried out in the preparation of the compounds of theinvention and the functional group to be protected, are within thecommon knowledge of the skilled person.

The removal of the optional protective groups is carried out accordingto conventional techniques.

For a general reference to the use of protective groups in orgamicchemistry, see Theodora W. Greene and Peter G. M. Wuts “Protectivegroups in organic synthesis”, John Wiley & Sons, Inc., II Ed., 1991.

The preparation of the salts of the compounds of formula I is carriedout according to known methods.

For the preparation of a single enantiomers or diastereoisomers, if thecase, of a compound of formula I, said compound may be obtained througha sterically controlled synthesis or by using reagents having theappropriate chirality or separating the desired isomer from theenantiomeric or diastereoisomeric mixture thereof according toconventional procedures. For instance, single optically activeenantiomers may be obtained from their racemates by chiralchromatography or by converting them into a mixture of diastereoisomericderivatives, separating the diastereoisomeric derivatives and restoringthe respective enantiomers.

Diastereoisomers can be separated from their mixtures by means ofconventional techniques based on their different physico-chemicalproperties, such as chromatography, distillation, or fractionalcrystallization.

Pharmacology

The compounds of the invention may be used for the manufacture of amedicament active as calcium and/or sodium channel modulator againstdisorders caused by dysfunctions of voltage gated calcium and/or sodiumchannels.

The activity of the compounds representative of this invention wascompared with that of our internal standard “ralfinamide”(S)-(+)-2-[4-(2-fluoro-benzyloxy)-benzylamino]-propanamide and/or“safinamide” (S)-(+)-2-[4-(3-fluoro-benzyloxy)-benzylamino]-propanamide.

Such compounds are voltage-dependent blockers of the calcium and/orsodium channels with potencies in the low micromolar range asdemonstrated by the blockade of the calcium and/or sodium influx(fluorescence assays) and by the voltage-dependent blockade of thecurrents (patch clamp techniques). The N-type and L-type calcium channelmodulating activity of the phenylethylamino derivatives was measuredthrough a fluorescence-based calcium influx assays (Table 1 for N-typeand Table 2 for L-type) and through patch clamp techniques inconstitutive and/or Cav 2.2 transfected cell lines (Table 4).

The sodium channel modulating activity of the phenylethylaminoderivatives was measured through a fluorescence-based sodium influxassay (Table 3), through patch clamp techniques in constitutive and/orNav 1.3 transfected cell lines (Table 5) and in cortical neurons (Table6).

The MAO-B activity of the above compounds was measured by using aradioenzymatic assay (Table 7).

The in vivo analgesic activity of the above compounds was assessed inthe “rat complete Freund's adjuvant model” and in the “Bennett model ofneuropathic pain in rats” (Table 8).

The anticonvulsant activity was measured using the “Maximal electroshocktest” in mice (Table 9).

The anti mania activity was measured using the “Amphetamine andchlordiazepoxide-induced hyperlocomotion in mice” model (FIG. 1).

The anti-schizophrenia and anti-addiction activities were assessed usingthe “test of cognitive impairment in schizophrenia” (Table 10) and the“Cocaine-induced behavioural sensitization test” in rats.

“Acute bladder irritation by acetic acid in rats” and “Intermediatebladder irritation by cyclophosphamide in rats” tests were used asmodels for urological diseases.

The anti migraine activity was measured using the “migraine test” inrats.

Such substances exhibit also “use and frequency-dependency”, i.e. anenhancement of the block during a high frequency stimulation when thereis a large accumulation of channels in the inactivated state, such as inneuronal pathological conditions. Functionally, the usedependent blockresults in depression of neuronal activity at high frequency firing andwith lower blocking capacity at normal firing rate suggesting that thecompounds of this invention may selectively depress abnormal activity ofthe calcium and/or sodium channels, leaving unaffected the physiologicalactivity, thus decreasing CNS depressant effects (W. A. Catterall,Trends Pharmacol. Sci. (1987) 8: 57-65).

The compounds of the invention are active in vivo when orally orintraperitoneally administered in the range of 0.1 to 100 mg/kg indifferent animal models here following described.

In view of the above described mechanisms of action, the compounds ofthe present invention are useful in the prevention or treatment ofneuropathic pain. Neuropathic pain syndromes include, and are notlimited to: diabetic neuropathy; sciatica; non-specific lower back pain;multiple sclerosis pain; fibromyalgia; HIV-related neuropathy;neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia,Morton's neuralgia, causalgia; and pain resulting from physical trauma,amputation, phantom limb, cancer, toxins or chronic inflammatoryconditions; central pain such as the one observed in thalamic syndromes,mixed central and pripheral forms of pain such as complex regional painsyndromes (CRPS) also called reflex sympathetic dystrophies.

The compounds of the invention are also useful for the treatment ofchronic pain. Chronic pain includes, and is not limited to, chronic paincaused by inflammation or an inflammatory-related condition,ostheoarthritis, rheumatoid arthritis, acute injury or trauma, upperback pain or lower back pain (resulting from systematic, regional orprimary spine disease such as radiculopathy), bone pain (due toosteoarthritis, osteoporosis, bone metastasis or unknown reasons),pelvic pain, spinal cord injury-associated pain, cardiac chest pain,non-cardiac chest pain, central post-stroke pain, myofascial pain,sickle cell pain, cancer pain, Fabry's disease, AIDS pain, geriatricpain or pain caused by headache, temporomandibular joint syndrome, gout,fibrosis or thoracic outlet syndromes, in particular rheumatoidarthritis and osteoarthritis.

The compounds of the invention are also useful in the treatment of acutepain (caused by acute injury, illness, sports-medicine injuries, carpaltunnel syndrome, burns, musculoskeletal sprains and strains,musculotendinous strain, cervicobrachial pain syndromes, dyspepsis,gastric ulcer, duodenal ulcer, dysmenorrhea, endometriosis or surgery(such as open heart or bypass surgery), post operative pain, kidneystone pain, gallbladder pain, gallstone pain, obstetric pain or dentalpain.

The compounds of the invention are also useful in the treatment ofheadaches such as migraine, tension type headache, transformed migraineor evolutive headache, cluster headache, as well as secondary headachedisorders, such as the ones derived from infections, metabolic disordersor other systemic illnesses and other acute headaches, paroxysmalhemicrania and the like, resulting from a worsening of the abovementioned primary and secondary headaches.

The compounds of the invention are also useful for the treatment ofneurological conditions such as epilepsy including simple partialseizure, complex partial seizure, secondary generalized seizure, furtherincluding absence seizure, myoclonic seizure, clonic seizure, tonicseizure, tonic clonic seizure and atonic seizure. The compounds of theinvention are also useful for the treatment of neurodegenerativedisorders of various origins such as Alzheimer Disease and otherdementia conditions such as Lewys body, fronto-temporal dementia andtaupathies; amyotrophic lateral sclerosis, Parkinson Disease and otherparkinsonian syndromes; other spino cerebellar degeneration andCharcot-Marie-Toot neuropathy.

The compounds of the invention are also useful for the treatment ofcognitive disorders and of psychiatric disorders. Psychiatric disordersinclude, and are not limited to major depression, dysthymia, mania,bipolar disorder (such as bipolar disorder type I, bipolar disorder typeII), cyclothymic disorder, rapid cycling, ultradian cycling, mania,hypomania, schizophrenia, schizophreniform disorders, schizoaffectivedisorders, personality disorders, attention disorders with or withouthyperactive behaviour, delusional disorders, brief psychotic disorders,shared psychotic disorders, psychotic disorder due to a general medicalcondition, substance-induced psychotic disorders or a psychotic disordernot otherwise specified, anxiety disorders such as generalised anxietydisorder, panic disorders, post-traumatic stress disorder, impulsecontrol disorders, phobic disorders, dissociative states and moreover insmoke, drug addiction and alcoholism. In particular bipolar disorders,psychosis, anxiety and addiction.

Compounds of the invention are also useful in the treatment of diseasessuch as vertigo, tinnitus, muscle spasm, muscular sclerosis, and otherdisorders including and not limited to cardiovascular diseases (such ascardiac arrhythmia, cardiac infarction or angina pectoris, hypertention,cardiac ischemia, cerebral ischemia) endocrine disorders (such asacromegaly or diabetes insipidus) diseases in which the pathophysiologyof the disorder involves excessive or hypersecretory or otherwiseinappropriate cellular secretion of an endogenous substance (such ascatecholamine, a hormone or a growth factor).

The compounds of the invention are also useful in the selectivetreatment of liver disease, such as inflammatory liver diseases, forexample chronic viral hepatitis B, chronic viral hepatitis C, alcoholicliver injury, primary biliary cirrhosis, autoimmune hepatitis,non-alcoholic steatohepatitis and liver transplant rejection.

The compounds of the invention inhibit inflammatory processes affectingall body systems. Therefore are useful in the treatment of inflammatoryprocesses of the muscular-skeletal system of which the following is alist of examples but it is not comprehensive of all target disorders:arthritic conditions such as alkylosing spondylitis, cervical arthritis,fibromyalgia, gut, juvenile rheumatoid arthritis, lumbosacral arthritis,osteoarthritis, osteoporosis, psoriatic arthritis, rheumatic disease;disorders affecting skin and related tissues: eczema, psoriasis,dermatitis and inflammatory conditions such as sunburn; disorders of therespiratory system: asthma, allergic rhinitis and respiratory distresssyndrome, lung disorders in which inflammation is involved such asasthma and bronchitis; chronic obstructive pulmonary disease; disordersof the immune and endocrinological systems: periarthritis nodosa,thyroiditis, aplastic anaemia, sclerodoma, myasthenia gravis, multiplesclerosis and other demyelinizating disorders, encephalomyelitis,sarcoidosis, nephritic syndrome, Bechet's syndrome, polymyositis,gingivitis.

Compounds of the invention are also useful in the treatment ofgastrointestinal (GI) tract disorders such as inflammatory boweldisorders including but not limited to ulcerative colitis, Crohn'sdisease, ileitis, proctitis, celiac disease, enteropathies, microscopicor collagenous colitis, eosinophilic gastroenteritis, or pouchitisresulting after proctocolectomy and post ileonatal anastomosis, andirritable bowel syndrome including any disorders associated withabdominal pain and/or abdominal discomfort such as pylorospasm, nervousindigestion, spastic colon, spastic colitis, spastic bowel, intestinalneurosis, functional colitis, mucous colitis, laxative colitis andfunctional dyspepsia; but also for treatment of atrophic gastritis,gastritis varialoforme, ulcerative colitis, peptic ulceration, pyresis,and other damage to the GI tract, for example, by Helicobacter pylori,gastroesophageal reflux disease, gastroparesis, such as diabeticgastroparesis; and other functional bowel disorders, such asnon-ulcerative dyspepsia (NUD); emesis, diarrhoea, and visceralinflammation.

Compounds of the invention are also useful in the treatment of disordersof the genito-urinary tract such as overactive bladder, prostatitis(chronic bacterial and chronic non-bacterial prostatitis), prostadynia,interstitial cystitis, urinary incontinence and benign prostatichyperplasia, annexities, pelvic inflammation, bartolinities andvaginitis. In particular overactive bladder and urinary incontinence.

The compounds of the invention are also useful in the treatment ofophthalmic diseases such as retinitis, retinopathies, uveitis and acuteinjury to the eye tissue, macular degeneration or glaucoma,conjunctivitis.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more other therapeuticagents. Examples of suitable agents for adjunctive therapy include aserotonin receptor modulator including a 5HT1B/1D agonist, such as atriptan (e.g. sumatriptan or naratriptan); an adenosine A1 agonist; anadenosine A2 antagonist; a purinergic P2X antagonist, an EP ligand; anNMDA modulator, such as a glycine antagonist; an AMPA modulator; asubstance P antagonist (e.g. an NK1 antagonist); a cannabinoid; anicotinic receptor agonist; an alpha-1 or 2 adrenergic agonist;acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; a leukotrienereceptor antagonist; a DMARD (e.g. methotrexate); gabapentin and relatedcompounds; L-dopa and/or dopamine agonists; acatechol-O-methyltransferase inhibitor; a tricyclic antidepressant (e.g.amitryptiline); a neurone stabilising antiepileptic drugs; amonoaminergic uptake inhibitor (e.g. venlafaxine); a matrixmetalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor,such as an iNOS or an nNOS inhibitor; a free radical scavenger; analpha-synuclein aggregation inhibitor; a cholinesterase inhibitor, acholesterol lowering agent; an alpha-secretase modulator; abetasecretase modulator; a beta-amyloid aggregation inhibitor; aninhibitor of the release, or action, of tumor necrosis factor alpha; anantibody therapy, such as monoclonal antibody therapy; an antiviralagent, such as a nucleoside inhibitor (e.g. lamivudine) or an immunesystem modulator (e.g. interferon); an opioid analgesic, such asmorphine; a vanilloid receptor antagonist; an analgesic, such as acyclooxygenase-1 and/or cyclooxygenase-2 inhibitor; a local anaestheticsuch as lidocaine and derivatives; a stimulant, including caffeine; anH2-antagonist (e.g. ranitidine); a proton pump inhibitor (e.g.omeprazole); an antacid (e.g. aluminium or magnesium hydroxide; anantiflatulent (e.g. semethicone); a decongestant (e.g. phenylephrine,phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine);antitussive (e.g. codeine, hydrocodone, carmiphen, carbetapentane, ordextramethorphan); a diuretic; or a sedating or non-sedatingantihistamine; other calcium or sodium channel blockers. It is to beunderstood that the present invention covers the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in combinationwith one or more therapeutic agents.

The compounds of the present invention are useful in human andveterinary medicaments. It is to be understood that as used herein theterms “treatment” or “treating” whenever not specifically definedotherwise, include prevention, alleviation and cure of pathologicalaffection, in particular, they include both treatment of establishedsymptoms and prophylactic treatment. The compounds of the presentinvention for their therapeutic or preventive use in the above mentionedpathologies will be preferably used as active ingredients in apharmaceutical composition.

Therefore, a further object of the present invention are pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof the invention or a salt thereof in admixture with a pharmaceuticallyacceptable carrier.

Accordingly, the expression “therapeutically effective” when referred toan “amount”, a “dose” or “dosage” of the compounds of this invention isintended as an “amount”, a “dose” or “dosage” of any said compoundssufficient for use in both treatment of the established symptoms and theprophylactic treatment of the above said pathological affections.

The pharmaceutical compositions object of the present invention may beadministered in a variety of immediate and modified release dosageforms, e.g. orally, in the form of tablets, troches, capsules, sugar orfilm coated tablets, liquid solutions, emulsions or suspensions;rectally, in the form of suppositories; parenterally, e.g. byintramuscular and/or depot formulations; intravenous injection orinfusion; locally and transdermally in form of patch and gel and cream.

Suitable pharmaceutically acceptable, therapeutically inert organicand/or inorganic carrier materials useful in the preparation of suchcomposition include, for example, water, gelatin, gum arabic, lactose,starch, cellulose, magnesium stearate, talc, vegetable oils,cyclodextrins, polyalkyleneglycols and the like.

The composition comprising the phenylethylamino derivatives of formula Ias above defined can be sterilized and may contain further well knowncomponents, such as, for example, preservatives, stabilizers, wetting oremulsifying agents, e.g. paraffin oil, mannide monooleate, salts toadjust osmotic pressure, buffers and the like.

For example, the solid oral forms may contain, together with the activeingredient, diluents, e.g. lactose, dextrose, saccharose, cellulose,corn starch or potato starch; lubricants, e.g. silica, talc, stearicacid, magnesium or calcium stearate, and/or polyethylene glycols;binding agents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose or polyvinyl pyrrolidone; disgregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents such aslecithin, polysorbates, laurylsulphates; and, in general, non-toxic andpharmacologically inactive substances used in pharmaceuticalformulations. Said pharmaceutical preparations may be manufactured inknown manner, for example, by means of mixing, granulating, tabletting,sugar-coating, or film-coating processes.

The preparation of the pharmaceutical compositions object of theinvention can be carried out according to common techniques.

The oral formulations comprise sustained release formulations that canbe prepared in conventional manner, for instance by applying an entericcoating to tablets and granules.

The liquid dispersion for oral administration may be e.g. syrups,emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as a carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethyl-cellulose, or polyvinyl alcohol. The suspensions orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g. sterilewater, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, ifdesired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusion may contain ascarrier, for example, sterile water or preferably they may be in theform of sterile, aqueous, isotonic saline solutions.

The suppositories may contain, together with the active ingredient, apharmaceutically acceptable carrier, e.g. cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactants orlecithin.

The pharmaceutical compositions comprising the phenylethylaminoderivatives of formula I as above defined will contain, per dosage unit,e.g., capsule, tablet, powder injection, teaspoonful, suppository andthe like from about 0.1 to about 500 mg of one or more activeingredients most preferably from 1 to 10 mg.

Optimal therapeutically effective doses to be administered may bereadily determined by those skilled in the art and will vary, basically,with the strength of the preparation, with the mode of administrationand with the advancement of the condition or disorder treated. Inaddition, factors associated with the particular subject being treated,including subject age, weight, diet and time of administration, willresult in the need to adjust the dose to an appropriate therapeuticallyeffective level.

It is to be understood that while the invention is described inconjunction of the preferred embodiments thereof, those skilled in theart are aware that other embodiment could be made without departing fromthe spirit of the invention.

Experimental Part

The ¹H-NMR spectra have been stored in solution of CDCl₃ or DMSO-d₆ witha Varian Gemini 200 MHz spectrometer. The chemical shifts are defined asd with CDCl₃ or DMSO-d₆ and D₂O as inner standard.

The HPLC/MS analyses are stored with a Gilson instrument by utilizing aX-Terra RP18 column (5 μm, 4.6×50 mm) coupled to a UV detector (220 nm)and a Finnigan Aqa mass spectrometer (electron spray, positiveionization mode). Conditions utilized for the analyses: flow: 1.2ml/min; column temperature: 50° C.; A/B elution gradient (eluent A: 0.1%formic acid in water; eluent B: 0.1% formic acid in acetonitrile): 5-95%of B from 0 to 8.0 minutes, 95% of B from 8.0 to 9.5 minutes.

For better illustrating the invention the following examples are nowgiven.

EXAMPLES Example 12-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 1

Step A [2-(4-Hydroxy-3-methoxy-phenyl)-ethyl]-carbamic acid tert-butylester

54 g (0.24 mol) of (Boc)₂O dissolved in 100 ml of dioxane were added at0° C. to a solution containing 39 g (0.23 mol) of2-(4-hydroxy-3-methoxy-phenyl)-ethylamine in 230 ml of 1M sodiumhydroxide and 390 ml of dioxane. The reaction was stirred at roomtemperature overnight. Dioxane was removed and aqueous KHSO₄ was addedto the residue, until a pH value of 6 was reached. Extraction with ethylacetate gave an oil that was triturated with hexane. 54.7 g (88% yield)of a white solid were obtained.

¹H-NMR CDCl₃: 7.26 (s, 1H); 6.88-6.64 (m, 2H); 5.51 (s, 1H); 4.54 (bs,1H); 3.80 (s, 3H); 3.41-3.27 (m, 2H); 2.72 (t, 2H, J=7.25 Hz); 1.44 (s,9H).

Step B [2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-carbamic acidtert-butyl ester

34.6 g (0.23 mol) of 1-chloromethyl-3-fluoro-benzene in 50 ml of drydimethylformamide were added to a suspension of 55.9 g (0.209 mol) of[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester,43 g of K₂CO₃ and 3.4 g of potassium iodide in 400 ml of drydimethylformamide. The reaction was stirred at room temperatureovernight. Solvent was removed, water was added to the residue and theproduct was extracted with ethyl acetate. The crude oil obtained wastriturated with diethyl ether. The solid was filtered and 58.2 g (74%yield) of the title product were obtained.

¹H-NMR CDCl₃: 7.40-6.60 (m, 7H); 5.10 (s, 2H); 4.50-4.60 (bs, 1H); 3.90(s, 3H); 3.30-3.40 (m, 2H); 3.75 (t, 2H, J=7.2 Hz); 1.44 (s, 9H).

Step C 2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylaminehydrochloride

58.2 g (0.155 mol) of2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-carbamic acidtert-butyl ester was dissolved in 300 ml of ethyl acetate. 150 ml ofanhydrous 2 M hydrochloric acid in ethyl acetate were added and themixture was stirred at room temperature overnight. The solid wasfiltered and washed with ethyl acetate and with diethyl ether and 44.2 g(91% yield) of a white solid were obtained.

¹H-NMR D₂O: 7.31-7.17 (m, 1H); 7.11-6.80 (m, 5H); 6.69-6.61 (m, 1H);5.02 (s, 2H); 3.69 (s, 3H); 3.05 (t, 2H, J=6.85 Hz); 2.74 (t, 2H, J=6.85Hz).

Step D [2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-aceticacid methyl ester hydrochloride

1 g (3.2 mmol) of2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamine, 833 mg (6 mmol)of K₂CO₃, 50 mg of potassium iodide and 0.27 ml (2.9 mmol) ofbromo-acetic acid methyl ester were dissolved in 10 ml ofdimethylformamide and the mixture was stirred at room temperatureovernight. Solvent was removed, water was added to the residue and theresidue was extracted with ethyl acetate. The crude product was purifiedby flash chromatography (dichloromethane/methanol/NH₃100:0:0→100:2.5:0.25 gradient v:v:v). The product obtained was dissolvedin anhydrous hydrochloric acid in ethyl acetate. The solvent was removedand the residue was triturated with diethyl ether. 482 mg (39% yield) ofthe title compound were obtained as a brown solid.

¹H-NMR CDCl₃: 7.39-7.28 (m, 2H); 7.22-6.92 (m, 2H); 7.04-6.92 (m, 1H);6.86-6.74 (m, 3H); 5.10 (s, 2H); 3.88 (s, 3H); 3.87-3.80 (m, 2H); 3.78(s, 3H); 3.41-3.19 (m, 4H).

Step E2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-acetamidehydrochloride

900 mg (2.34 mmol) of[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-acetic acidmethyl ester were dissolved in 10 ml of dry toluene and 5 ml (10 mmol)of a 2 M solution of methylamine in tetrahydrofuran were added at 0° C.,followed by 5 ml (10 mmol) of a 2 M solution of trimethyl aluminium inheptane. The reaction was stirred at room temperature overnight. Thesolution was cooled down to 0° C. and poured into methanol. The solventwas removed and the crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→100:4:0.4 gradient v:v:v). Theproduct was dissolved in anhydrous hydrochloric acid in ethyl acetate,and the solid was filtered. 590 mg (66% yield) of the title compoundwere isolated as a hygroscopic solid.

¹H-NMR dimethylsulfoxide-d₆: 9.06 (m, 2H); 8.46 (bm, 1H); 7.49-6.67 (m,7H); 5.07 (s, 2H); 3.76 (s, 3H); 3.73-3.63 (bm, 2H); 3.23-3.04 (m., 2H);2.94-2.80 (bm, 2H); 2.65 (d, 3H, J=4.36 Hz).

LC-MS: MH⁺=347.4

Example 22-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-isobutylamino]-N-methyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 2

90 mg of2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-acetamide(0.235 mmol) and 19 mg (0.263 mmol) of 2-methyl-propionaldehyde weredissolved in 6 ml of a dichloromethane/acetic acid (8:2, v:v) mixtureand 1.5 ml of methanol. 100 mg (0.425 mmol) of(polystyrylmethyl)trimethylammonium cyanoborohydride (loading: 4.25mmol/g) were added and the mixture was stirred at room temperatureovernight. The resin was filtered and the solvent was removed. The crudeproduct was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→100:2:0.2 gradient v:v:v). Theproduct was dissolved in anhydrous hydrochloric acid in ethyl acetate,the solvent was removed and the residue was triturated with diethylether. 80 mg (77% yield) of the title compound were isolated as ahygroscopic solid.

¹H-NMR dimethylsulfoxide-d₆: 9.42 (bm, 1H); 8.73 (bm, 1H); 7.49-6.72 (m,7H); 5.07 (s, 2H); 4.14-3.87 (m, 2H); 3.77 (s, 3H); 3.42-3.24 (m, 2H);3.10-2.86 (m, 4H); 2.69-2.65 (m, 3H); 2.16-1.92 (m, 1H); 0.95 (d, 6H).

LC-MS: MH⁺=403

Examples 3-13. These compounds were prepared analogously according tothe procedure described in Scheme 2.

Example 32-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(2-propyn-1-yl)amino]N-methyl-acetamidehydrochloride

LC-MS: MH⁺=385

Example 42-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(3-methyl-isoxazol-5-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=442

Example 52-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(3-methoxy-isoxazol-5-ylmethyl)amino]-N-methyl-acetamidehydrochloride Example 62-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(1-methyl-imidazol-5-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=441

Example 72-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=431

Example 82-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=401

Example 92-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=427

Example 102-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(furan-3-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=427

Example 112-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(5-hydroxymethylfuran-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=457

Example 122-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-[(1,2,3-thiadiazol-4-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=445

Example 132-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(1,3-dimethyl-pyrazol-5-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=455

Examples 14-15. These compounds were prepared analogously, according tothe procedure described in Scheme 2, but were not salified withhydrochloric acid.

Example 142-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(6-methoxy-pyridin-3-ylmethyl)amino]-N-methyl-acetamide

LC-MS: MH⁺=468

Example 152-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(3,5-dimethoxybenzyl)amino]-N-methyl-acetamide

LC-MS: MH⁺=497

Examples 16-25. These compounds were prepared analogously, according tothe procedure described in Scheme 2 of Example 2 starting from2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-acetamideinstead of2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-acetamide.

Example 162-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-methylamino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=375

Example 172-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=415

Example 182-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-isopropylamino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=403

Example 192-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(1-methyl-piperidin-4-yl)amino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=458

Example 202-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=451

Example 212-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-ethylamino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=389

Example 222-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=441

Example 232-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(thien-2-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=457

Example 242-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(thiazol-2-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=458

Example 252-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(pyridin-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

LC-MS: MH⁺=452

Examples 26-27. These compounds were prepared analogously according tothe procedure described in Scheme 2, starting from2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-acetamideinstead of2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-acetamide,but were not salified with hydrochloric acid.

Example 262-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(2-hydroxyethyl)amino]-N,N-dimethyl-acetamide

LC-MS: MH⁺=405

Example 272-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(thiazol-2-yl)amino]-N,N-dimethyl-acetamideExample 282-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 3

100 mg (0.26 mmol) of2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-acetic acidmethyl ester were dissolved in 5 ml of dry toluene. 0.4 ml (0.8 mmol) ofa 2 M solution of dimethylamine solution in tetrahydrofuran was added at0° C., followed by 0.4 ml (0.8 mmol) of a 2 M solution of trimethylaluminium in heptane. The reaction was stirred for 4 hours at roomtemperature. The solution was cooled down to 0° C. and poured intomethanol. The solvent was removed and the crude residue was purified byflash chromatography (dichloromethane/methanol/NH₃ 100:5:0.5 v:v:v). Theproduct was dissolved in ethyl acetate/hydrochloric acid. The solventwas removed and the residue was triturated with diethyl ether. 70 mg(68% yield) of the title compound were isolated as a hygroscopic solid.

¹H-NMR CDCl₃: 9.56 (bs, 1H); 7.38-7.27 (m, 2H); 7.21-7.10 (m, 2H);7.04-6.86 (m, 2H); 6.79-6.76 (m, 2H); 5.10 (s, 2H); 3.93 (t broad, 2H);3.89 (s, 3H); 3.41-3.15 (m, 4H); 2.94 (s, 6H)

LC-MS: MH⁺=361

Example 292-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1-(pyrrolidin-1-yl)-ethanonehydrochloride

This compound was prepared as described in Scheme 3 using pyrrolidine indimethylformamide instead of N,N-dimethylamine, to obtain the desiredcompound as a white solid (yield 48%).

¹H-NMR CDCl₃: 9.57 (s broad, 1H); 7.38-7.27 (m, 2H); 7.21-7.10 (m, 2H);7.04-6.76 (m, 4H); 5.10 (s, 2H); 3.89 (s, 3H); 3.84 (t broad, 2H);3.50-3.14 (m, 8H); 2.07-1.80 (m, 4H)

LC-MS: MH⁺=387

Example 302-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-propionamidehydrochloride

The above compound was synthesized according to Scheme 4

Step A2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-propionicAcid Methyl Ester hydrochloride

A solution of 0.75 g (2.4 mmol) of2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamine, 0.88 ml (5.05mmol) of di-isopropylethylamine and 0.294 ml (2.64 mmol) of2-bromo-propionic acid methyl ester in 10 ml of dry tetrahydrofuran waskept at 75° C. for 48 hours. The reaction mixture was poured into waterand the product was extracted with ethyl acetate. The solvent wasremoved and the crude residue was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→100:2:0.2 gradient). The productwas dissolved in ethyl acetate/hydrochloric acid. The solvent wasremoved and the residue was triturated with diethyl ether. 300 mg (31%yield) of a white solid were isolated.

¹H-NMR D₂O: 7.35-7.18 (m, 1H); 7.16-6.80 (m, 5H); 6.75-6.62 (m, 1H);5.05 (s, 2H); 4.06-3.88 (m, 1H); 3.77-3.64 (m, 6H); 3.18 (bt, 2H), 2.83(bt, 2H); 1.43-1.34 (m, 3H)

Step B2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-propionamidehydrochloride

125 mg (0.31 mmol) of2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-propionicacid methyl ester were dissolved in 5 ml of dry toluene. 0.785 ml (1.57mmol) of a 2 M solution of dimethylamine in tetrahydrofuran were addedat 0° C., followed by 0.47 ml (0.94 mmol) of a 2 M solution of trimethylaluminium in heptane. The reaction was stirred for 5 hours at roomtemperature. The solution was cooled down to 0° C. and poured intomethanol. The solvent was removed and the crude product was purified byflash chromatography (dichloromethane/methanol/NH₃ 100:5:0.5). Theproduct was dissolved in ethyl acetate/hydrochloric acid. The solventwas removed and the solid was filtered. 94 mg (74% yield) of the titlecompound were isolated as a hygroscopic solid.

¹H-NMR CDCl₃: 8.01 (bs, 1H); 7.38-7.09 (m, 3H); 7.03-6.72 (m, 4H); 5.08(s, 2H); 4.49-4.30 (m, 1H); 3.86 (s, 3H); 3.42-3.07 (m, 4H); 2.98 (d,6H, J=7.51 Hz); 1.69-1.60 (m, 3H).

Example 31(S)-2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-4-methyl-valeramide

LC-MS: MH⁺=403

This compound was prepared analogously, according to the proceduredescribed in Scheme 4

Example 322-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-2-phenyl-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 5

Step A2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-2-phenyl-aceticAcid Methyl Ester

A solution of 0.75 g (2.4 mmol) of2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamine, 0.88 ml (5.05mmol) of di-isopropylethylamine and 0.416 ml (2.64 mmol) of2-bromo-2-phenyl-acetic acid methyl ester in 10 ml of drytetrahydrofuran was kept at 75° C. for 48 hours. The reaction mixturewas poured into water and the product was extracted with ethyl acetate.The crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→100:2:0.2 gradient v:v:v). 600 mg(50% yield) of the title compound were obtained as a yellow oil.

¹H-NMR D₂O: 7.45-7.16 (m, 6H); 7.10-6.84 (m, 3H); 6.81-6.70 (m, 2H);6.57 (dd, 1H, J=8.37 and 2.16 Hz); 4.99 (s, 2H); 4.93 (s, 1H); 3.63 (d,6H, J=2.38 Hz); 3.13-2.68 (m, 4H).

Step B2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-2-phenyl-acetamide

This compound was synthesized according to the procedure described inScheme 6, step B, using 115 mg of2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-2-phenyl-aceticacid methyl ester (0.27 mmol), 1.06 ml (2.1 mmol) of a 2 M solution ofdimethylamine in tetrahydrofuran and 0.53 ml (1.06 mmol) of a 2 Msolution of trimethyl aluminium in heptane. 66 mg (52% yield) of thetitle compound were isolated as a white solid.

¹H-NMR CDCl₃: 8.52 (bs, 1H); 7.47-7.10 (m, 9H); 7.03-6.92 (m, 2H);6.81-6.62 (m, 3H); 5.42 (bs, 1H); 5.10 (s, 2H); 3.58 (s, 3H); 3.24-2.99(m, 4H); 2.91 (d, 6H)

Example 33-35: These compounds were prepared according to the proceduredescribed in Scheme 5 using the relevant amine in step B.

Example 332-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1-(morpholin-4-yl)-2-phenyl-ethanonehydrochloride

(yield 51%).

¹H-NMR CDCl₃: 8.59 (bs, 1H); 7.48-7.26 (m, 6H); 7.21-7.10 (m, 2H);7.04-6.92 (m, 2H); 6.79-6.63 (m, 3H); 5.50 (bs, 1H); 5.09 (s, 2H); 3.85(s, 3H); 3.76-3.33 (m, 6H); 3.23-2.91 (m, 6H).

Example 342-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1-(pyrrolidin-1-yl)-2-phenyl-ethanonehydrochloride

LC-MS: MH⁺=463

Example 352-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1-(4-methylpiperazin-1-yl)-2-phenyl-ethanonehydrochloride

LC-MS: MH⁺=492

Example 362-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-acetamidehydrochloride

The above compound was synthesized according to Scheme 6

Step A [2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamine

A mixture of 4.4 g (16 mmol) of2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamine, 1.72 g (16 mmol)of benzaldehyde, 100 ml of ethanol and 30 g of 4 Å molecular sieves wasrefluxed overnight. The reaction mixture was cooled down to roomtemperature, 50 mg of PtO₂ were added and the mixture was hydrogenatedat 15 psi for 5 hours. The catalyst was filtered off and the solvent wasremoved under reduced pressure. The crude reaction product was purifiedby flash chromatography (dichloromethane/methanol/NH₃ 85:15:1.5, v:v:v)and 2.72 g (46% yield) of the title compound were isolated as a yellowoil.

¹H-NMR CDCl₃: 10.12 (bs, 1H); 7.60-7.26 (m, 8H); 7.19-7.09 (m, 2H);7.03-6.91 (m, 1H); 6.77-6.59 (m, 3H); 5.08 (s, 2H); 4.01 (t broad, 2H);3.18-2.88 (m, 4H).

Step B2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-aceticAcid Methyl Ester

1.7 g (4.65 mmol) of[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamine, 1.74 ml(10 mmol) of di-isopropylethylamine and 0.5 ml (5.11 mmol) of2-bromo-acetic acid methyl ester were dissolved in 20 ml of acetonitrileand the reaction was stirred at 70° C. overnight. The solvent wasremoved under reduced pressure, water was added to the residue and theproduct was extracted with ethyl acetate. The crude product was purifiedby flash chromatography (hexane/ethyl acetate 100:0→80:20 gradient v:v)and 1.94 g (95% yield) of the title compound were isolated as a yellowoil.

¹H-NMR CDCl₃: 7.72-7.65 (m, 2H); 7.47-7.28 (m, 5H); 7.21-7.10 (m, 2H);7.04-6.93 (m, 1H); 6.85-6.67 (m, 3H); 5.11 (s, 2H); 4.68-4.30 (m, 2H);3.89 (s, 3H); 3.72 (s, 3H); 3.68-3.15 (m, 6H).

Step C2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-acetamidehydrochloride

80 mg (0.18 mmol) of2-[[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-aceticacid methyl ester were dissolved in 3 ml of dioxane and 2 ml of NH₃ 30%.The solution was heated with microwaves at 100° C. for 8 hours. Thesolvent was removed and the crude reaction residue was purified by flashchromatography (dichloromethane/methanol/NH₃ 100:0:0→95:5:0.5 gradientv:v:v). The product was dissolved in anhydrous hydrochloric acid inethyl acetate. The solvent was removed and the residue was trituratedwith diethyl ether. 30 mg (36% yield) of the title compound wereisolated as a yellow solid.

¹H-NMR dimethylsulfoxide-d₆: 10.00 (bs, 1H); 7.95, 7.69 (2 bs, 2H);7.63-6.67 (m, 12H); 5.06 (s, 2H); 4.42 (bs, 2H); 3.86 (bs, 2H); 3.75 (s,3H); 3.38-3.12 (bs., 2H); 3.10-2.87 (bs., 2H).

LC-MS: MH⁺=423

Examples 37-45. These compounds were prepared according to the proceduredescribed in Scheme 6 step C, using the relevant amine

Example 372-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-ethylacetamidehydrochloride

LC-MS: MH⁺+=451

Example 382-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-isopropyl-acetamidehydrochloride

LC-MS: MH⁺=465

Example 392-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-ethylN-methyl-acetamidehydrochloride

LC-MS: MH⁺=465

Example 402-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-1-(pyrrolidin-1-yl)-ethanonehydrochloride

LC-MS: MH⁺=477

Example 412-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-Nbenzyl-acetamidehydrochloride

LC-MS: MH⁺=513

Example 422-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-amino-2-methyl-propyl)-acetamidehydrochloride

LC-MS: MH⁺=494

Example 432-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-dimethylamino-ethyl)-acetamidehydrochloride

LC-MS: MH⁺=494

Example 442-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-acetamidehydrochloride

LC-MS: MH⁺=534

Example 452-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(3-imidazol-1-yl-propyl)-acetamidehydrochloride

LC-MS: MH⁺=531

Example 462-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-methyl-acetamide

This compound was prepared analogously, according to the proceduredescribed in Scheme 6 step C, using the relevant amine, but was notsalified with hydrochloric acid.

LC-MS: MH⁺=437.4

Example 472-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-ethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 7

Step A[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amine

A suspension of 0.66 g (2.1 mmol) of2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamine, 0.151 g (2.1mmol) of cyclopropanecarbaldehyde, 0.3 ml of triethylamine and 3 g ofmolecular sieves in 6 ml of ethanol was stirred under reflux for 3hours. The mixture was cooled to 0° C. and 0.2 g (5 mmol) of NaBH₄ wasadded portionwise. The reaction mixture was stirred at room temperatureovernight. 3 ml of aqueous ammonium chloride were added, the solvent wasremoved under reduced pressure and the residue was extracted with ethylacetate. The crude residue was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→95:5:0.5 gradient v:v:v) to get0.3 g of the desired compound as an oil (43% yield).

¹H-NMR CDCl₃: 9.80 (bm, 2H); 7.37-6.67 (m, 7H); 5.09 (s, 2H); 3.86 (s,3H); 3.22 (bs, 4H); 2.92-2.80 (m, 2H); 0.93-0.78 (m, 1H); 0.75-0.63 (m,2H); 0.49-0.38 (m, 2H).

Step B2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)-amino]-aceticacid methyl ester

0.271 g (0.82 mmol) of[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amine,0.140 ml (1 mmol) of triethylamine and 0.155 g (0.89 mmol) ofbromo-acetic acid methyl ester were dissolved in 5 ml of acetonitrileand the reaction was carried out at 70° C. overnight. Solvent wasremoved under vacuum, water was added to the residue and the product wasextracted with ethyl acetate. The crude product was purified by flashchromatography (hexane/ethyl acetate 100:0→80:20 gradient v:v) and 0.32g (97% yield) of the title compound was isolated as a yellow oil.

¹H-NMR CDCl₃: 7.38-7.28 (m, 1H); 7.22-7.10 (m, 2H); 7.04-6.91 (m, 1H);6.80-6.62 (m, 3H); 5.11 (s, 2H); 3.88 (s, 3H); 3.70 (s, 3H); 3.59-3.50(m, 2H); 3.00-2.53 (m, 6H); 0.96-0.78 (m, 1H); 0.58-0.46 (m, 2H);0.18-0.07 (q broad, 2H).

Step C2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-ethyl-acetamide

105 mg (0.26 mmol) of2-[[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-aceticacid methyl ester were dissolved in 5 ml of dry toluene. 0.5 ml of a 2 M(1 mmol) solution of ethylamine in tetrahydrofuran were added at 0° C.,followed by 0.4 ml (0.8 mmol) of a 2 M solution of trimethyl aluminiumin heptane. The reaction was stirred for 4 hours at room temperature.The solution was cooled to 0° C. and poured into methanol. The solventwas removed and the crude product was purified by flash chromatography(ethyl acetate/hexane 0:100→85:15 gradient v:v) to obtain 52 mg (48%yield) of the title compound as a hygroscopic solid.

LC-MS: MH⁺=415

¹H-NMR CDCl₃: 8.85 (bs, 1H); 7.39-6.64 (m, 7H); 5.09 (s, 2H); 4.19 (m,2H); 3.86 (s, 3H); 3.61-3.42 (m, 2H); 3.42-3.09 (m, 6H); 1.36-1.17 (m,1H); 1.22 (t, 3H, J=7.3 Hz); 0.81-0.65 (m, 2H); 0.53-0.41 (m, 2H).

Example 482-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-isopropyl-acetamidehydrochloride

This compound was prepared according to the procedure described hereabove using isopropyl amine instead of ethyl amine. 63 mg of the desiredcompound (52% yield) were isolated as a hygroscopic solid.

LC-MS: MH⁺=429

Example 492-[[2-[4-(Benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide

The above compound was synthesized according to Scheme 8

Step A [2-(4-Benzyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amine

A suspension of 1.5 g (5.1 mmol) of2-(4-benzyloxy-3-methoxy-phenyl)-ethylamine, 0.365 g (5.1 mmol) ofcyclopropanecarboxaldehyde, 0.7 ml of triethylamine and 8 g of molecularsieves in 15 ml of ethanol was stirred under reflux for 3 hours. Themixture was cooled down to 0° C. and 0.19 g (5 mmol) of NaBH₄ was addedportionwise. The reaction mixture was stirred at room temperatureovernight. 3 ml of aqueous ammonium chloride were added, the solvent wasremoved under vacuum and the residue was extracted with ethyl acetate.The crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→95:5:0.5 gradient v:v:v) to get0.850 g (53% yield) of the desired compound as an oil.

LC-MS: MH⁺=312

Step B2-[[2-[4-(Benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide

A mixture of 0.5 g (1.6 mmol) of[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amine, 0.27ml (1.92 mmol) of triethylamine, 0.207 g (1.92 mmol) of2-chloro-N-methyl-acetamide in 4 ml of dimethylformamide was heated withmicrowaves to 120° C. for 2 hours. The solvent was removed under vacuumand the crude was purified by flash chromatography (ethyl acetate/hexane0:10→9:1 gradient). 0.52 g (84% yield) of the title compound wasisolated as a yellow solid.

¹H-NMR CDCl₃: 7.49-6.62 (m, 8H); 5.14 (s, 2H); 3.88 (s, 3H); 3.14 (s,2H); 2.83-2.58 (m, 4H); 2.52 (d, 3H, J=5.58 Hz); 2.43 (d, 2H, J=6.62Hz); 0.91-0.69 (m, 1H.); 0.57-0.44 (m, 2H); 0.1-0.05 (m, 2H)

LC-MS: MH⁺=383

Example 502-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 9

Step A [2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amine

A suspension of 0.264 g (1 mmol) of 2-(3-benzyloxy-phenyl)-ethylamine,70 mg (1 mmol) of cyclopropanecarboxaldehyde, and 5 g of molecularsieves in 4 ml of ethanol was stirred under reflux for 3 hours. Themixture was cooled to 0° C. and 37.8 mg (1 mmol) of NaBH₄ were addedportionwise. The reaction mixture was stirred at room temperatureovernight. 3 ml of aqueous ammonium chloride were added, the solvent wasremoved under vacuum and the residue was extracted with ethyl acetate.The crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→95:5:0.5 gradient v:v:v) to get0.24 g (85% yield) of the desired compound as a yellow oil.

¹H-NMR CDCl₃: 7.48-6.78 (m, 9H); 5.06 (s, 2H); 3.00-2.71 (m, 4H); 2.50(d, 2H); 1.03-0.81 (m, 1H); 0.55-0.41 (m, 2H); 0.16-0.06 (m, 2H).

Step B2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamidehydrochloride

A mixture of 0.24 g (0.85 mmol) of[2-(3-benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amine, 0.14 ml (1.00mmol) of triethylamine, 0.11 g (1.02 mmol) of2-chloro-N-methyl-acetamide in 3 ml of dimethylformamide was heated withmicrowaves to 120° C. for 2 hours. The solvent was removed and the cruderesidue was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→95:5:0.5 gradient). The productobtained was dissolved in anhydrous hydrochloric acid in ethyl acetate,the solvent was removed under vacuum and the residue was triturated withdiethyl ether. 0.24 g (80% yield) of the title compound was isolated asa yellow solid.

¹H-NMR CDCl₃: 7.47-6.68 (m, 9H); 5.06 (s, 2H); 3.15 (s, 2H); 2.86-2.62(m, 4H); 2.56 (d, 3H); 2.43 (d, 2H); 0.92-0.67 (m, 1H); 0.59-0.44 (m,2H); 0.16-0.04 (m, 2H)

LC-MS: MH⁺=353

Example 512-[[2-(3-Benzyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 10

Step A [2-(3-Benzyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amine

A suspension of 30.2 g (133 mmol) of 2-(3-benzyloxy-phenyl)-ethylamine,11.0 ml (133 mmol) of furan-2-carboxaldehyde, and 60 g of 4 Å molecularsieves in 300 ml of ethanol was kept under reflux for 3 hours. Themixture was cooled to 0° C. and 10.8 g (286 mmol) of NaBH₄ were addedportionwise. The reaction mixture was stirred at room temperatureovernight. 60 ml of aqueous ammonium chloride were added, the solventwas removed under vacuum and the residue was extracted with ethylacetate. The crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:1:0.1 v:v:v) and 22.4 g (55% yield) ofthe title compound were isolated as a yellow oil.

¹H-NMR CDCl₃: 10.1 (b, 1H); 7.4-6.3 (m, 12H); 5 (s, 2H); 4.2 (t, 2H,J=4.9 Hz); 3.2-3.0 (m, 4H).

Step B2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(furan-2-ylmethy)amino]-N-methyl-acetamidehydrochloride

A solution of 3.0 g (9.8 mmol) of[2-(3-benzyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amine, 15.0 g (10.7mmol) of 2-chloro-N-methyl-acetamide and 1.87 ml (10.7 mmol) ofdiisopropylethylamine in 50 ml of acetonitrile was stirred under refluxfor 24 hours. The solvent was removed under reduced pressure and thecrude reaction mixture was purified by flash chromatography (ethylacetate/hexane 1:1 v:v). The product isolated was dissolved in anhydroushydrochloric acid in ethyl acetate. The solvent was removed under vacuumand the residue was triturated with diethyl ether. 2.66 g (65% yield) ofthe title compound were isolated as a hygroscopic solid.

¹H-NMR CDCl₃: 8.8 (b, 1H); 7.5-7.2 (m, 7H); 6.9-6.8 (m, 4H); 6.5 (m,1H); 5.0 (s, 2H); 4.5-4.3 (m, 2H); 4.0-3.8 (m, 2H); 3.2 (m, 4H); 3-2.8(m, 3H)

LC-MS: MH⁺=379

Example 522-[[2-[3-(2-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 11

Step A2-[[2-(3-Hydroxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide

400 mg of Pd/C (10%) were added to a solution of 4.12 g (10.9 mmol) of2-[[2-(3-benzyloxyphenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride in 100 ml of methanol. The hydrogenation was carried outat 30 psi for 90 minutes at room temperature. The catalyst was filteredoff, the solvent was removed and the crude product was purified by flashchromatography (ethyl acetate/hexane 1:1+triethylamine). 2.1 g (67%yield) of the title compound were isolated as a white solid.

¹H-NMR CDCl₃: 7.37 (d, 1H, J=2.1); 7.20 (t, 1H, J=7.2); 6.75-6.67 (m,4H); 6.33-6.31 (m, 1H); 6.20 (m, 1H); 5.72 (b, 1H); 3.72 (s, 2H); 3.14(s, 2H); 2.74 (m, 4H); 2.56 (d, 3H, J=4.1).

LC-MS: MH⁺=289

Step B2-[[2-[3-(2-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methylacetamidehydrochloride

A solution of 60 mg (0.21 mmol) of2-[[2-(3-hydroxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide,36 mg (0.25 mmol) of 1-chloromethyl-2-fluoro-benzene, 44 mg of K₂CO₃(0.32 mmol) and 3 mg of potassium iodide in 4 ml of dimethylformamidewas refluxed overnight. The solvent was removed under vacuum and thecrude product was purified by preparative HPLC. The isolated product wasdissolved in ethyl acetate/hydrochloric acid. The solvent was removedunder vacuum and the residue was triturated with diethyl ether. 65 mg(72% yield) of the title compound were isolated as a white solid.

¹H-NMR CDCl₃: 12.67 (b, 1H); 8.79 (m, 1H); 7.55-7.05 (m, 5H); 6.88 (m,4H); 6.49 (m, 1H); 5.11 (s, 2H); 4.45 (m, 2H); 3.72 (m, 2H); 3.24 (m,4H); 2.88 (d, 3H, J=4.56 Hz).

LC-MS: MH⁺=397.3

Examples 53-68. These compounds were prepared according to the proceduredescribed in Scheme 11 using the relevant reagents.

Example 532-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride Example 542-[[2-[3-(2-Chloro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=413

Example 552-[[2-[3-(3-Chloro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=413

Example 562-[[2-[3-(3-Methyl-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=393

Example 572-[[2-[3-(4-Methyl-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=393

Example 582-[[2-[3-(3-Trifluoromethyl-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=447

Example 592-[[2-[3-(3-Fluoro-phenoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methylacetamidehydrochloride

LC-MS: MH⁺=383

Example 602-[[2-[3-(2-Phenyl-ethoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methylacetamidehydrochloride

LC-MS: MH⁺=393

Example 612-[[2-(3-Cyclopropylmethoxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=343

Example 622-[[2-[3-(2-Piperidin-1-yl-ethoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=340

Example 632-[[2-[3-(2-Morpholin-4-yl)-ethoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=402

Example 642-[[2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=371

Example 652-[[2-[3-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=398

Example 662-[[2-[3-(5-Chloro-thien-2-ylmethoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=419

Example 672-[[2-[3-(Pyridin-2-ylmethoxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=380

Examples 68-69. These compounds were prepared analogously, according tothe procedure described in Scheme 11, using the relevant reagents, butwere not salified with hydrochloric acid.

Example 682-[[2-[3-(4-Trifluoromethyl-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide

LC-MS: MH⁺=447

Example 692-[[2-(3-Cyclopentyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methylacetamide

LC-MS: MH⁺=357

Example 702-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-acetamide

The above compound was synthesized according to Scheme 12

Step A [2-(3-Benzyloxy-phenyl)-ethyl]-carbamic acid tert-butyl ester

4.8 g of (Boc)₂O (22 mmol) in 10 ml of dichloromethane were added to asuspension of 5.27 g of 2-(3-benzyloxy-phenyl)-ethylamine-HCl (20 mmol)in 20 ml of dichloromethane and 2.78 ml of triethylamine (20 mmol). Thereaction was stirred for 1 hour at room temperature. After evaporationof the solvent, an aqueous solution containing 5% citric acid was addedto the residue and the product was extracted with ethyl acetate. Thetitle product was isolated as a colorless oil in quantitative yield.

¹H-NMR CDCl₃: 7.45-6.78 (m, 9H); 5.05 (s, 2H); 4.54 (bs, 1H); 3.48-3.28(m, 2H); 2.77 (t, 2H); 1.44 (s, 9H).

Step B [2-(3-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester

1 g of Pd/C 10% was added to a solution of 13 g (0.039 mol) of[2-(3-benzyloxy-phenyl)ethyl]-carbamic acid tert-butyl ester in 100 mlof ethanol. The mixture was hydrogenated at 40 psi overnight. Thecatalyst was filtered off and washed with ethanol. The solvent wasremoved under vacuum and 9.4 g of the title compound were obtained as acolourless oil in quantitative yield.

¹H-NMR CDCl₃: 7.22-7.12 (m, 1H); 6.78-6.66 (m, 3H); 4.56 (bs, 1H);3.42-3.30 (m, 2H); 2.74 (t, 2H); 1.44 (s, 9H).

Step C [2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-carbamic acidtert-butyl ester

2.87 g (19.8 mmol) of 1-chloromethyl-3-fluoro-benzene in 5 ml of drydimethylformamide were added to a suspension of 4.66 g (19.6 mmol) of[2-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester, 4 g ofK₂CO₃ and 0.3 g of potassium iodide in 50 ml of dry dimethylformamide.The reaction was first stirred at room temperature overnight, then washeated up to 50° C. for 6 hours. After evaporation of the solvent, waterwas added to the residue and the product was extracted with ethylacetate. 7 g of crude oil were obtained. Purification by flashchromatography using a mixture of ethyl acetate/hexane (1:9→2:8gradient) gave 5.9 g (86% yield) of the title product as a colourlessoil.

¹H-NMR CDCl₃: 7.40-6.68 (m, 8H); 5.05 (s, 2H); 4.53 (bs, 1H); 3.44-3.30(m, 2H); 2.77 (t, 2H); 1.44 (s, 9H).

Step D 2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethylamine

A solution of 10.36 g (30 mmol) of[2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-carbamic acid tert-butyl esterin 100 ml of dichloromethane and 15 ml of trifluoroacetic acid wasstirred at room temperature overnight. The solvent was removed, a 5%K₂CO₃ solution in water was added and the product was extracted withethyl acetate to obtain the title compound in quantitative yield as asticky oil.

¹H-NMR dimethylsulfoxide-d₆: 8.04 (bs, 3H); 7.49-6.72 (m, 8H); 5.09 (s,2H); 3.08-2.75 (m, 4H).

Step E [2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amine

1.44 g (15 mmol) of furan-2-carboxaldehyde and 7.5 g of molecular sieves3 Å were added to a solution of 2.45 g (10 mmol) of2-[3-(3-fluoro-benzyloxy)-phenyl]-ethylamine in 50 ml of dry ethanol.The reaction mixture was refluxed for 3 hours. The molecular sieves werefiltered off and the solution was cooled to 5° C. 0.57 g (15 mmol) ofNaBH₄ was added under N₂ and the reaction was stirred at roomtemperature overnight. Solvent was removed, a 5% NaHCO₃ aqueous solutionwas added to the residue and the product was extracted with ethylacetate. The crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→100:2:0.2, v:v:v). 2.2 g (68%yield) of an oil were obtained.

¹H-NMR CDCl₃: 7.44-6.12 (m, 11H); 5.04 (s, 2H); 3.79 (s, 2H); 2.96-2.73(m, 4H).

Step F2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-acetamide

A solution of 1.8 g (5.53 mmol) of[2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amine, 0.57g (6.08 mmol) of 2-chloro-acetamide and 0.92 ml (6.62 mmol) oftriethylamine in 5 ml of dry dimethylformamide was heated at 120° C. for2 hours with microwaves. Solvent was removed under vacuum, water wasadded and the product was extracted with ethyl acetate. The crudereaction mixture was purified by flash chromatography(dichloromethane/methanol 95:5 v:v). 2.1 g (99% yield) of a yellow oilwere isolated.

¹H-NMR DMSO-d⁶: 7.84-6.48 (m, 11H); 5.08 (s, 2H); 4.48 (s, 2H); 3.87 (s,2H); 3.33-2.87 (m, 4H).

Example 712-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-dimethylamino-ethyl)-acetamideDihydrochloride

The above compound was synthesized according to Scheme 13

Step A2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-aceticAcid Methyl Ester

0.46 g (3.05 mmol) of 2-bromo-acetic acid methyl ester were added to asolution of 0.9 g (2.76 mmol) of[2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amine and0.39 g (3.05 mmol) of di-isopropylethylamine in 15 ml of acetonitrile.Solvent was removed, water was added to the residue and the product wasextracted with ethyl acetate. Purification by flash chromatography(ethyl acetate/hexane 1:9→2:8 gradient v:v) gave 0.9 g (82% yield) of aclear oil.

¹H-NMR CDCl₃: 7.40-7.11 (m, 5H); 7.06-6.94 (m, 1H); 6.83-6.74 (m, 3H);6.33-6.29 (m, 1H); 6.20 (d, 1H, J=3.34 Hz); 5.04 (s, 2H); 3.90 (s, 2H);3.70 (s, 3H); 3.40 (s, 2H); 2.92-2.72 (m, 4H).

Step B2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-dimethylamino-ethyl)-acetamideDihydrochloride

100 mg (0.25 mmol) of2-[[2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-aceticacid methyl ester were dissolved in 5 ml of dry toluene. 66 mg (0.75mmol) of N,N-dimethyl-ethane-1,2-diamine were added at 0° C. followed by0.4 ml (0.8 mmol) of 2 M triethyl aluminium in heptane. The reactionmixture was heated to 60° C. overnight. The solution was cooled at 0° C.and poured into methanol. The solvent was removed under vacuum and thecrude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:2:0.2, v:v:v). The product wasdissolved in ethyl acetate/hydrochloric acid, and the solid obtained wasfiltered. 80 mg (65% yield) of the title compound were isolated ashygroscopic solid.

¹H-NMR D₂O: 7.48-6.29 (m, 1H); 4.95 (s, 2H); 4.33 (s, 2H); 3.88 (s, 2H);3.48-3.34 (m, 2H); 3.32-3.17 (m, 2H); 3.15-3.04 (m, 4H); 2.97-2.77 (m,2H); 2.72 (s, 6H)

Example 722-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-amino-2-methyl-propyl)-acetamideDihydrochloride

100 mg (0.25 mmol) of2-[[2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-aceticacid methyl ester and 1 ml of 2-methyl-propane-1,2-diamine were heatedat 120° C. for 3 hours with microwaves. The reaction mixture was cooledto room temperature, water was added and the product was extracted withethyl acetate. The crude product was purified by flash chromatography(dichloromethane/methanol 95:5 v:v). The product was dissolved in ethylacetate/hydrochloric acid, the solvent was removed and the resultingsalt was triturated with diethyl ether. 95 mg (72% yield) of the titlecompound were isolated as a hygroscopic solid.

¹H-NMR CDCl₃: 10.95 (bs, 1H); 9.13 (bs, 1H); 8.46 (bs, 3H); 7.47-6.32(m, 11H); 4.99 (s, 2H); 4.89-4.45 (m, 2H,); 4.45-4.09 (bs, 2H);3.87-3.00 (m, 6H); 1.52 (s, 6H).

LC-MS: MH⁺=454

Examples 73-76: These compounds were prepared according to the proceduredescribed in Scheme 13 using the relevant amines

Example 732-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-methoxy-ethyl)-acetamidehydrochloride

LC-MS: MH⁺=441

Example 742-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(1,3,4-thiadiazol-2-yl)-acetamidehydrochloride

LC-MS: MH⁺=467

Example 752-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(3-methyl-isoxazol-5-yl)-acetamidehydrochloride

LC-MS: MH⁺=464

Example 762-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(1H-pyrazol-3-yl)-acetamidehydrochloride

LC-MS: MH⁺=449

Examples 77-78. These compounds were prepared according to the proceduredescribed in Scheme 13 using the relevant amine, but were not salifiedwith hydrochloric acid.

Example 772-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(1H-imidazol-2-yl)-acetamide

LC-MS: MH⁺=449

Example 782-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-thiazol-2-yl-acetamide

LC-MS: MH⁺=466

Example 792-[[2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-isopropylamino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 14

2-([2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-isopropylamino)-N,N-dimethyl-acetamidehydrochloride

19.6 mg (0.49 mmol) of NaH 60% in mineral oil were added to a solutionof 100 mg (0.378 mmol) of2-[[2-(3-hydroxy-phenyl)-ethyl]-isopropylamino]-N,N-dimethyl-acetamideand 0.102 g, (0.49 mmol) of 1,1,1-trifluoro-2-iodo-ethane in 4 ml DMF.The reaction was heated at 60° C. overnight. The solvent was removed,water was added and the product was extracted with ethyl acetate. Thecrude reaction mixture was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:0:0→100:2.5:0.25 gradient, v:v:v). Theproduct was dissolved in anhydrous hydrochloric acid in ethyl acetate,the solvent was removed and the product was triturated with diethylether. 18 mg (12.5% yield) of the title compound were isolated as awhite solid.

LC-MS: MH⁺=347

Example 802-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-propionamidehydrochloride

The above compound was synthesized according to Scheme 15

Step A2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-propionicAcid Methyl Ester

A solution of 562 mg (2 mmol) of[2-(3-benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amine, 0.3 ml (2.2mmol) of triethylamine and 367 mg (2.2 mmol) of 2-bromo-propionic acidmethyl ester in 20 ml of acetonitrile was refluxed for 24 hours. Solventwas removed, water was added and the product was extracted with ethylacetate. 730 mg of the title compound were isolated in quantitativeyield as a colourless oil.

¹H-NMR CDCl₃: 7.48-6.75 (m, 9H); 5.05 (s, 2H); 3.74 (q, 1H); 3.67 (s,3H); 3.00-2.37 (m, 6H); 1.24 (d, 3H); 0.96-0.74 (m, 1H); 0.60-0.40 (m,2H); 0.22-0.04 (m, 2H).

LC-MS: MH⁺=368

Step B2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-propionamidehydrochloride

730 mg (2 mmol) of2-[[2-(3-benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)-amino]-propionicacid methyl ester were dissolved in 10 ml of dry toluene. 4 ml (8 mmol)of methylamine solution 2 M in tetrahydrofuran were added, followed by 4ml (8 mmol) of 2 M trimethyl aluminium in heptane. The reaction wasstirred at room temperature overnight. The solution was cooled to 0° C.and poured into methanol. The solvent was removed under vacuum and thecrude reaction mixture was purified by flash chromatography(dichloromethane/methanol 100:5 v:v). The product was dissolved inanhydrous hydrochloric acid in ethyl acetate and the resulting salt wasfiltered. 500 mg (62% yield) of the title compound were isolated as ahygroscopic solid.

¹H-NMR CDCl₃: 7.48-6.69 (m, 9H); 5.06 (s, 2H); 3.56 (q, 1H); 2.80-2.14(m, 6H); 2.47 (d, 3H); 1.17 (d, 3H); 0.89-0.65 (1H); 0.63-0.37 (m, 2H);0.21-0.02 (m, 2H).

LC-MS: MH⁺=366

Example 812-[[2-[3-Methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 16

Step A2-[[2-(4-Hydroxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide

A mixture of 0.49 g (1.28 mmol) of2-[[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamideand 50 mg of Pd/C 10% in 10 ml of ethanol was hydrogenated at 40 psi for2 hours. The catalyst was filtered off and the solvent was removed.0.366 g (98% yield) of a yellow oil were isolated.

LC-MS: MH⁺=293

Step B:2-[[2-(3-Methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamidehydrochloride

A mixture of 90 mg (0.3 mmol) of2-[[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide,107 mg (0.51 mmol) of 1,1,1-trifluoro-2-iodo-ethane, 71 mg (0.51 mmol)of K₂CO₃ and 5 mg of potassium iodide in 5 ml of dimethylformamide washeated at 120° C. overnight. The mixture was filtered trough celite andthe solvent was removed under vacuum. The crude product was purified byflash chromatography (dichloromethane/methanol 100:0→100:1.5 gradient,v:v). The product was dissolved in anhydrous hydrochloric acid in ethylacetate, the solvent was removed under vacuum and the product wastriturated with diethyl ether. 30 mg (27% yield) of the title compoundwere isolated as a white hygroscopic solid.

¹H-NMR CDCl₃: 11.49 (bs, 1H); 8.48 (bs, 1H); 6.92-6.70 (m, 3H); 4.35 (q,2H, JHF=8.89 Hz); 4.21 (d, 2H); 3.84 (s, 3H); 3.66-3.10 (m, 6H); 2.85(d, 3H, J=4.62 Hz); 1.37-1.17 (m, 1H); 0.81-0.69 (m, 2H); 0.53-0.42 (m,2H)

LC-MS: MH⁺=374

Example 822-[[2-(4-Cyclopentyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamidehydrochloride

This compound was prepared according to the procedure described inScheme 16 using the relevant reagent.

¹H-NMR CDCl₃: 11.54 (bs, 1H); 8.84 (bs, 1H); 6.80-6.69 (m, 3H); 4.70 (m,1H); 4.17 (bd, 2H); 3.82 (s, 3H); 3.59-3.11 (m, 6H); 2.85 (d, 3H, J=4.55Hz); 1.96-1.53 (m, 8H); 1.33-1.18 (m, 1H); 0.81-0.71 (m, 2H); 0.51-0.43(m, 2H)

LC-MS: MH⁺=361

Example 832-[[2-(3′-Fluoro-biphenyl-3-yl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 17

Step A2-[[2-(3-Trifluoromethylsulfonyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide

1.36 g (3.8 mmol) of N-phenyl-bis(trifluoromethanesulfonimide) in 10 mlof acetonitrile were added under N₂ to a mixture of 1 g (3.5 mmol) of2-[[2-(3-hydroxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamideand 960 mg (7 mmol) of K₂CO₃ in 30 ml of acetonitrile/dichloromethane2:1 mixture. The solution was stirred at room temperature overnight. Thesolvent was removed under vacuum, water was added and the product wasextracted with ethyl acetate. The crude reaction mixture was purified byflash chromatography (hexane/ethyl acetate/dimethylformamide 1:2:0.2).1.3 g (90% yield) of the title compound were isolated as a yellow oil.

LC-MS: MH⁺=421

Step B2-[[2-(3′-Fluoro-biphenyl-3-yl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

A mixture of 100 mg (0.24 mmol) of2-[N-(3-trifluoromethylsulfonyloxyphenyl)-ethyl]-(furan-2-ylmethyl)amino)-N-methyl-acetamide,48 mg (0.34 mmol) of 3-fluoro-phenyl-boronic acid, 46 mg (0.34 mmol) ofK₂CO₃ and 10 mg of Pd(PPh₃)₄ in 2 ml of ethanol was heated at 110° C.with microwaves for 15 minutes. The mixture was filtered trough celiteand the solvent was removed under vacuum. The crude product was purifiedby preparative HPLC. The product was dissolved in anhydrous hydrochloricacid in ethyl acetate. The solvent was removed under vacuum and theproduct was triturated with diethyl ether. 34 mg (36% yield) of thetitle compound were isolated as a white solid.

¹H-NMR CDCl₃: 8.79 (b, 1H); 7.56-6.81 (m, 10H); 6.51-6.48 (m, 1H);4.61-4.35 (m, 2H); 3.77 (bs, 2H); 3.40-3.25 (m, 4H); 2.89 (d, 3H, J=4.6Hz).

LC-MS: MH⁺=367

Example 84-91: These compounds were prepared according to the proceduredescribed in Scheme 17 using the relevant boronic acid reagent.

Example 842-[[2-[3-(Thien-3-yl-)-phenyl)]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=355

Example 852-[[2-(3′-Methoxy-biphenyl-3-yl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=379

Example 862-[[2-(3′-Acetylamino-biphenyl-3-yl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=406

Example 872-[[2-(2′-Dimethylaminomethyl-biphenyl-3-yl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=406

Example 882-[[2-[3-(Pyridin-3-yl)-phenyl)]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=350

Example 892-[[2-[3-(6-Methoxy-pyridin-3-yl)-phenyl)]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=380

Example 902-[[2-[3-(2,4-Dimethoxy-pyrimidin-5-yl)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

LC-MS: MH⁺=411

Example 912-[[2-[3-(Furan-3-yl)-phenyl)]-ethyl]-(furan-2-ylmethyl)-amino]-N-methylacetamidehydrochloride

LC-MS: MH⁺=339

Example 922-[[2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide

This compound was prepared according to the procedure described inScheme 17 using the relevant boronic acid reagent but were not salifiedwith hydrochloric acid.

LC-MS: MH⁺=368

Example 932-[[2-[3-(piperidin-1-yl)-phenyl)]-ethyl]-(furan-2-ylmethyl)amino]-N-methylacetamidehydrochloride

A mixture of 100 mg (0.24 mmol) of2-[2-[(3-trifluoromethylsulfonyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino)-N-methyl-acetamide,41 mg (0.48 mmol) of piperidine, 28 mg (0.29 mmol) of sodiumter-butoxide, 10 mg of Pd(CH₃COO)₂ and 10 mg ofN-phenyl-2-(di-tbutylphosphinyl)-indole in 2 ml of toluene was heated at100° C. with microwaves for 15 minutes. The reaction mixture wasfiltered through celite and the solvent was removed under vacuum. Thecrude reaction mixture was purified by preparative HPLC. The product wasdissolved in anhydrous hydrochloric acid in ethyl acetate, the solventwas removed under reduced pressure and the product was triturated withdiethyl ether. 51 mg (55% yield) of the title compound were isolated asa yellow solid.

¹H-NMR CDCl₃: 8.66 (m, 1H); 8.10 (bs, 1H); 7.72-7.66 (m, 2H); 7.51-7.33(m, 2H); 6.86-6.84 (m, 1H); 6.50-6.47 (m, 1H); 4.55-4.52 (m, 2H);3.86-3.65 (m, 4H); 3.34 (bs, 6H); 2.83 (d, 3H, J=4.9 Hz); 2.72-2.65 (m,2H); 2.09-1.92 (m, 5H)

LC-MS: MH⁺=356

Example 942-[[2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 18

Step A 2-[2-(3-Benzyloxy-phenyl)-ethylamino]-N,N-dimethyl-acetamide

A mixture of 4.32 g (19 mmol) of 2-(3-benzyloxy-phenyl)-ethylamine, 7.9ml (57 mmol) of triethylamine, 1.95 ml (19 mmol) of2-chloro-N,N-dimethyl-acetamide and 332 mg (2 mmol) of potassium iodidein 110 ml of dry dimethylformamide was heated at 80° C. for 3 hours.Solvent was removed under vacuum and the crude reaction mixture waspurified by flash chromatography (dichloromethane/methanol/NH₃100:3:0.5, v:v:v). 3 g (51% yield) of the title compound were isolatedas a yellow solid.

LC-MS: MH⁺=313

Step B2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

1.06 g (22 mmol) of NaBH₄ were added portionwise to a mixture 2.9 g (9.3mmol) of 2-[2-(3-benzyloxy-phenyl)-ethylamino]-N,N-dimethyl-acetamide,1.28 ml (14.1 mmol) of tetrahydrofuran-3-carbaldehyde and 4 g of 4 Åmolecular sieves in 130 ml of 1,2-dichloroethane. The reaction mixturewas stirred at room temperature overnight. Aqueous ammonium chloride wasadded, the solvent was removed under vacuum, the residue was extractedwith ethyl acetate and the organic phase was washed with an aqueoussaturated solution of K₂CO₃. The solvent was removed under reducedpressure and the product was dissolved in anhydrous an hydroushydrochloric acid in ethyl acetate. The solvent was removed and theproduct was triturated with diethyl ether. 3.2 g (80% yield) of thetitle compound were isolated as a yellow solid.

¹H-NMR CDCl₃: 7.45-7.32 (m, 5H); 7.23-7.19 (m, 1H); 6.89-6.85 (m, 3H);5.05 (s, 2H); 4.14-2.98 (m, 14H); 2.92 and 2.86 (2s, 6H); 2.82-2.71 (m,1H).

LC-MS: MH⁺=397

Example 952-[[2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 19

Step A2-[[2-(3-Hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide

A mixture of 2.4 g (6.05 mmol) of2-[[2-(3-benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamideand 200 mg of Pd/C 10% in methanol/acetic acid 10:1 (70 ml) washydrogenated 18 hours at 60 psi. The catalyst was filtered off and thesolvent was removed under vacuum. The crude reaction mixture waspurified by flash chromatography (dichloromethane/methanol/NH₃ 97:3:0.3,v:v:v). 1.63 g (88% yield) of the title compound were isolated as ayellow oil.

LC-MS: MH⁺=307

Step B2-[[2-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

A mixture of 100 mg (0.33 mmol) of2-[[2-(3-hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide,139 mg (0.66 mmol) of 1,1,1-trifluoro-2-iodo-ethane, 90 mg (0.66 mmol)of K₂CO₃ and 5 mg of potassium iodide in 4 ml of dimethylformamide wasrefluxed overnight. The mixture was filtered through celite and thesolvent was removed under vacuum. The crude reaction mixture waspurified by preparative HPLC. The product was dissolved in ethylacetate/hydrochloric acid, the solvent was removed and the product wastriturated with diethyl ether. 18 mg (13% yield) of the title compoundwere isolated as a yellow solid.

LC-MS: MH⁺=389

Example 962-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 20

A solution of2-[[2-(3-hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide(1.0 g 3.3 mmol), 1-bromobutane (0.43 ml, 4 mmol), potassium carbonate(680 mg 5 mmol), potassium iodine (50 mg, 0.3 mmol), in DMF (30 ml) wasrefluxed for 16 h. After filtration over celite pad, the solution wasevaporated from the solvent and the crude oil obtained purified bypreparative HPLC. The hydrochloride salt was prepared by adding HCl 1Nin AcOEt to the free amine dissolved in ethyl ether. After filtration,690 mg (50% yield) the title compound was obtained as a white solid of99% purity.

¹H-NMR (CDCl₃) 12.54 (broad signal, 1H); 7.25-6.73 (m, 4H); 4.28-3.16(m, 12H); 3.93 (t, 2H); 2.92 (s, 3H); 2.87 (s, 3H); 2.85-2.67 (m, 1H);2.36-1.86 (m, 2H); 1.83-1.66 (m, 2H); 1.58-1.38 (m, 2H); 0.97 (t, 3HJ=8.3 Hz)

LC-MS: MH⁺=363.43

Example 96bis2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethylAcetamide (R) and (S) Enantiomers

The racemic mixture of2-[[2-(3-butoxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride obtained according to Example 96 was separated using thechiral column CHIRALPAC® AD 20 μm−250×21 mm, mobile phasemethanol/diethylamine 100/0.1 (v/v), flow rate 20 ml/min detection UV275 nm, temperature 25° C.

The retention time of the first and the second eluted enantiomer,obtained as a honey-like yellowish bases, was 5.2 min and 6.7 minrespectively. The [α]_(D) of the first eluted enantiomer is −10°, c=0.1,MeOH (20° C.) and the [α]D of the second eluted enantiomer is: +10°,c=0.1, MeOH (20° C.)

The enantiomeric excess of both was >99.5%

Example 972-[[2-(3-Butoxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride

This compounds was prepared according to the procedure described inScheme 20 starting from2-[[2-(3-hydroxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamideprepared as described in the Example 52

LC-MS: MH⁺=345

Example 982-[[2-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 21

Step A 1-Fluoro-4-methyl-2-(2,2,2-trifluoro-ethoxy)-benzene

1.05 g (26 mmol) of NaH 60% were added portionwise to a solution of 2.9g (23 mmol) of 2-fluoro-5-methyl-phenol in 15 ml of drydimethylformamide. The mixture was stirred at room temperature for 30minutes. 6.35 g (25 mmol) of toluene-4-sulfonic acid2,2,2-trifluoro-ethyl ester were added and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto water and extracted with diethyl ether. The crude product waspurified by flash chromatography (hexane/ethyl acetate 9:1, v:v) to give2.7 g (56% yield) of the title compound.

¹H-NMR CDCl₃: 7.05-6.77 (m, 3H); 4.40 (q, 2H, JH-F=8.48 Hz); 2.31 (s,3H)

Step B 4-Bromomethyl-1-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzene

A mixture of 2.68 g (12.8 mmol) of1-fluoro-4-methyl-2-(2,2,2-trifluoro-ethoxy)-benzene, 2.3 g (12.9 mmol)of NBS and 140 mg of dibenzoylperoxide in 60 ml of CCl₄ was refluxed for6 hours. Solvent was removed and the crude residue was used without anyfurther purification for the next step.

Step C [4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetonitrile

900 mg (13.8 mmol) of KCN were added to a solution of 3.3 g (11.5 mmol)of 4-bomomethyl-1-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzene in 30 ml ofdry dimethylsulfoxide. The reaction mixture was stirred for 1 hour atroom temperature. Water was added and the product was extracted withdiethyl ether. The solvent was removed under vacuum and the cruderesidue was purified by flash chromatography (hexane/ethyl acetate 8:2v:v). 1.4 g (52% yield) of the title compound were isolated as a whitesolid.

¹H-NMR CDCl₃: 7.21-6.92 (m, 3H); 4.41 (q, 2H, JH-F=8.48 Hz); 3.68 (s,2H)

Step D 2-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethylamine

800 mg (10 mmol) of borane-methyl sulfide complex were added to asolution of 1.23 g (5.27 mmol) of[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetonitrile in 50 ml ofdry tetrahydrofuran. The reaction mixture was refluxed for 4 hours.Solvent was removed and then water was added. A first extraction withdiethyl ether allowed to partially purify the crude reaction mixture.The resulting aqueous layer was then basified with NH₄OH, and theproduct was extracted with dichloromethane. After removal of the solvent1 g (80% yield) of the title compound was isolated as a yellow solid.

¹H-NMR CDCl₃: 7.10-6.98 (m, 1H); 6.92-6.80 (m, 2H); 4.42 (q, 2H,JH-F=8.5 Hz); 4.42 (q, 2H); 2.95 (t, 2H, J=6.55 Hz); 2.70 (t, 2H, J=6.55Hz)

Step E[2-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amine

A mixture of 500 mg (2.1 mmol) of2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethylamine, 210 mg (2.1mmol) of tetrahydrofuran-3-carbaldehyde and 2 g of 4 Å molecular sievesin 30 ml of dry dichloromethane was stirred at room temperature for 30minutes. 630 mg (2.9 mmol) of NaBH(OAc)₃ were added portionwise. Thereaction mixture was stirred for 4 hours at room temperature. An aqueous5% solution of NaHCO₃ was added and the product was extracted withdichloromethane. The crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:9:0.5 v:v:v). 300 mg (44% yield) ofthe title compound were isolated as an oil.

¹H-NMR CDCl₃: 7.09-6.97 (m, 1H); 6.92-6.81 (m, 2H); 4.41 (q, 2H,JH-F=8.7 Hz); 3.90-3.66 (m, 3H); 3.51-4.40 (m, 1H); 2.91-2.59 (m, 6H);2.54-2.24 (m, 1H); 2.11-1.92 (m, 1H); 1.64-1.46 (m, 1H)

Step F2-[[2-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

A mixture of 85 mg (0.26 mmol) of[2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amine,0.06 ml of triethylamine and 48 mg (0.39 mmol) of2-chloro-N,N-dimethyl-acetamide in 3 ml of dimethylformamide was heatedfor 1 hour to 120° C. with microwaves. The solvent was removed undervacuum. The crude product was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:3:0.3 v:v:v). The product wasdissolved in anhydrous hydrochloric acid in ethyl acetate, the solventwas removed under reduced pressure and the product was triturated withdiethyl ether. 74 mg (65% yield) of the title compound were isolated asa brown solid.

¹H-NMR CDCl₃: 7.07-6.80 (m, 3H); 4.41 (q, 2H); 3.77 (m, 3H); 3.50 (m,1H); 3.33 (bm, 2H); 2.98-2.32 (m, 13H); 1.94 (m, 1H); 1.54 (m, 1H)

LC-MS: MH⁺=407

Example 992-[[2-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-1-pyrrolidin-1-yl-ethanonehydrochloride

This compound was obtained as a brown solid in 74% yield following thesame procedure described in Scheme 21 for the synthesis of2-[[2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide,using 2-chloro-1-pyrrolidin-1-yl-ethanone as the reagent instead of2-chloro-N,N-dimethyl-acetamide.

¹H-NMR CDCl₃: 7.05-6.81 (m, 3H), 4.43 (q, 2H), 3.77 (m, 3H), 3.54-3.31(m, 7H), 3.01-2.33 (m, 7H), 2.06-1.77 (m, 5H), 1.58 (m, 1H)

LC-MS: MH⁺=433

Example 1002-[[2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 22

Step A [2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amine

A solution of dihydro-furan-3(2H)-one in 50 ml of dichloromethane wasadded to a suspension of 1.99 g (7.5 mmol) of2-(3-benzyloxy-phenyl)-ethylamine and 1.05 ml (7.5 mmol) oftriethylamine in 70 ml of 1,2-dichloroethane. The mixture was stirred atroom temperature for 15 minutes then 3.2 g (15.1 mmol) of NaBH(CH₃COO)₃were added portionwise. The reaction mixture was stirred at roomtemperature overnight. Water was added and the reaction mixture wasextracted with dichloromethane Solvent was removed under vacuum and thecrude residue was purified by flash chromatography(dichloromethane/methanol/NH₃ 100:3:0.9 v:v:v). 1.35 g (60% yield) ofthe title compound were isolated as a brown solid.

¹H-NMR CDCl₃: 7.47-7.15 (m, 6H), 6.87-6.79 (m, 3H), 5.03 (s, 2H),4.07-3.93 (m, 1H), 3.86-3.69 (m, 3H), 3.59-3.47 (m, 1H), 3.03-2.93 (m,4H), 2.26-1.85 (m, 2H)

LC-MS: MH⁺=298

Step B2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide

A mixture of 0.8 g (2.69 mmol) of[2-(3-benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amine, 0.56 ml(4.03 mmol) of triethylamine and 0.415 ml (4.03 mmol) of2-chloro-N,N-dimethyl-acetamide in 5 ml of dry dimethylformamide washeated to 120° C. for 2 hours with microwaves. Solvent was removed undervacuum and the crude residue was purified by flash chromatography(dichloromethane/methanol: 100:3, v:v). 0.611 g (59% yield) of the titlecompound were isolated as a yellow oil.

LC-MS: MH⁺=383

Step C2-[[2-(3-Hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide

A mixture of 0.61 g (1.59 mmol) of2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamideand 60 mg of Pd/C 10% in 10 ml of ethanol was hydrogenated for 2 hoursat 40 psi. The catalyst was filtered off and the solvent was removedunder vacuum. The crude residue was triturated with diethyl ether andfiltered. 0.45 g (96% yield) of a yellow solid were isolated.

¹H-NMR CDCl₃: 7.18-7.06 (m, 1H); 6.78-6.65 (m, 3H); 6.50 (bs, 1H);4.04-3.90 (m, 1H); 3.84-3.64 (m, 4H); 3.59-3.35 (m, 2H); 3.03-2.87 (s+m,7H); 2.80-2.67 (m, 2H); 2.13-1.83 (m, 2H)

LC-MS: MH⁺=293

Step D2-[[2-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamidehydrochloride

A mixture of 124 mg (0.424 mmol) of[[2-(3-hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide,178 mg (0.848 mmol) of 1,1,1-trifluoro-2-iodo-ethane, 117 mg (0.854mmol) of K₂CO₃ and 5 mg of potassium iodide in 4 ml of dimethylformamidewas heated for 2 hours to 120° C. with microwaves. The mixture wasfiltered through celite and the solvent was removed under vacuum. Thecrude residue was purified by flash chromatography(dichloromethane/methanol 100:0→100:2 gradient, v:v). The product wasdissolved in anhydrous hydrochloric acid in ethyl acetate, the solventwas removed under reduced pressure and the product was triturated withdiethyl ether. 20 mg (13% yield) of the title compound were isolated aswhite solid.

LC-MS: MH⁺=375

Example 1012-[[2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide

The above compound was synthesized according to Scheme 23

Step A2-[[2-(3-Trifluoromethylsulfonyloxy-phenyl)-ethyl]-(tetrahydrofuran-2-yl)amino]-N,N-dimethyl-acetamide

164 mg (0.451 mmol) of N-phenyl-bis(trifluoromethanesulfonimide) in 2 mlof acetonitrile were added under N₂ to a mixture of 120 mg (0.41 mmol)of2-[[2-(3-hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamideand 113 mg (0.82 mmol) of K₂CO₃ in 3 ml of acetonitrile. The reactionmixture was stirred at room temperature overnight. The solvent wasremoved under vacuum, water was added and the product was extracted withethyl acetate. 150 mg (86% yield) of the title compound were isolated asa yellow oil.

LC-MS: MH⁺=425

Step B2-[[2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamidehydrochloride

A mixture of 280 mg (0.66 mmol) of2-[[(3-trifluoromethylsulfonyloxy-phenyl)-ethyl]-(tetrahydrofuran-2-yl)amino]-N,N-dimethyl-acetamide,81 mg (0.57 mmol) of 3,5-dimethoxyisoxazole-4-boronic acid, 80 mg (0.58mmol) of K₂CO₃ and 10 mg of Pd(PPh₃)₄ in 4 ml of ethanol was heated at110° C. with microwaves for 15 minutes. The mixture was filtered throughcelite and the solvent was removed under vacuum. The crude product waspurified by flash chromatography (dichloromethane/methanol 100:0) 100:3gradient). The product was dissolved in anhydrous HCl in ethyl acetate.The solvent was then removed under reduced pressure and the product wastriturated with diethyl ether. 85 mg (0.21 mmol, yield: 31%) of thetitle compound were isolated as a white solid.

¹H-NMR CDCl₃: 7.44-7.12 (m, 4H); 4.57-4.39 (bs, 1H); 4.39-3.72 (m, 7H);3.61-3.05 (m, 3H); 2.99 (m, 6H); 2.74-2.51 (m, 1H); 2.41 (s, 3H);2.37-2.24 (m, 1H), 2.27 (s, 3H)

LC-MS: MH⁺=372

Example 1022-[[2-(3-Piperidin-1-yl-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

The above compound was synthesized according to Scheme 24

Step A2-[[2-(3-Trifluoromethylsulfonyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide

943 mg (2.64 mmol) of N-phenyl-bis(trifluoromethanesulfonimide) in 4 mlof acetonitrile were added under N₂ to a mixture of 735 mg (2.4 mmol) of2-[[2-(3-hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamideand 664 mg (4.8 mmol) of K₂CO₃ in 15 ml of acetonitrile. The reactionmixture was stirred at room temperature overnight. The solvent wasremoved under vacuum, water was added and the product was extracted withethyl acetate. The crude product was purified by flash chromatography(hexane/ethyl acetate/triethylamine 1:2:0.2, v:v:v). 399 mg (38% yield)of the title compound were isolated as a yellow oil.

LC-MS: MH⁺=439

Step B2-[[2-(3-Piperidin-1-yl-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide

A mixture of 129 mg (0.29 mmol) of2-[[(3-trifluoromethyl-sulfonyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide,50 mg (0.58 mmol) of piperidine, 34 mg (0.35 mmol) of sodiumtert-butoxide, 10 mg of Pd(OAc)₂ and 10 mg of N-phenyl-2-(di-t-butylphosphinyl)-indole in 2 ml of toluene was heated to 110° C. withmicrowaves for 15 minutes. The mixture was filtered through celite andthe solvent was removed under vacuum. The crude product was purified bypreparative HPLC, dissolved in anhydrous HCl in ethyl acetate and thesolvent was removed under reduced pressure. The product was trituratedwith diethyl ether. 23 mg (19% yield) of the title compound wereisolated as a yellow solid.

¹H-NMR CDCl₃: 7.94-7.91 (m, 2H); 7.49-7.29 (m, 2H); 4.00-3.10 (m, 17H);3.01 (s, 3H); 2.99 (s, 3H); 2.80-2.60 (m, 3H); 2.29-2.19 (m, 1H);1.97-1.90 (m, 4H)

LC-MS: MH⁺=374

Example 1032-[[2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride

A mixture of 135 mg (0.31 mmol) of2-[[(3-trifluoromethylsulfonyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide,61 mg (0.43 mmol) of 3,5-dimethylisoxazole-4-boronic acid, 59 mg (0.43mmol) of K₂CO₃ and 10 mg of Pd(PPh₃)₄ in 3 ml of ethanol was heated at110° C. with microwaves for 15 minutes. The mixture was filtered throughcelite and the solvent was removed. The crude residue was purified bypreparative HPLC. The product was dissolved in ethylacetate/hydrochloric acid, the solvent was removed and the product wastriturated with diethyl ether. 44 mg (34% yield) of the title compoundwere isolated as a white solid.

¹H-NMR CDCl₃: 7.43-7.13 (m, 4H); 4.17-3.28 (m, 12H); 2.98 (s, 3H); 2.96(s, 3H); 2.88-272 (m, 1H); 2.40 (s, 3H); 2.26 (s, 3H); 2.42-2.16 (m, 2H)

LC-MS: MH⁺=386

Example 104(2S)-2-[2-[(4-Benzyloxy)-phenyl]-1-methyl-ethylamino]-propionamidehydrochloride

The above compound was synthesized according to Scheme 25

3.0 g (25 mmol) of L-alanine hydrochloride, 3 g (12.5 mmol) of1-[(4-benzyloxy)-phenyl]-propan-2-one, 1.33 g (12.5 mmol) of Na₂CO₃ and2 g of 4 Å molecular sieves in 150 ml of methanol were stirred at 40° C.for 2 hours under nitrogen. 0.63 g (9.60 mmol) of NaBH₃CN were thenadded at room temperature and the mixture was stirred at roomtemperature overnight an. The vessel content was filtered, the solid waswashed with methanol, the organic filtrated concentrated to a smallvolume and the residue was passed on a flash chromatography(chloroform/methanol/NH₃ 95:5:0.5 v:v:v). 2.94 g (58% yield) of a 7:3diastereoisomeric mixture of the title compound was obtained bycrystallizeation from ethyl acetate.

¹H-NMR CDCl₃+CF₃COOD 7.40 (m, 5H); 7.05 (m, 4H); 5.06 (s, 2H); 4.20 (m,1H); 3.70-2.60 (m, 3H); 1.55 (d, 3H, J=7 Hz); 1.30 (d, 3H, J=6 Hz).

Example 105 N-Type Calcium Channel Influx Assay

IMR32 human neuroblastoma cells constitutively express both L- andN-type channels. Under differentiating conditions, IMR32 cellspreferentially express on the membrane surface N-type calcium channels.The remaining L-type calcium channels were blocked using the selectiveL-type blocker nifedipine. In these experimental conditions only N-typechannels can be detected. IMR32 cells were differentiated using 1 mMdibutyrril-cAMP and 2.5 μM bromodeoxyuridine for 8 days (4 times) in 225cm² flask, then detached, seeded at 200,000 cells/well on 96poly-Llysine-coated plates and further incubated for 18-24 h in thepresence of differentiating buffer before use.

The Ca²⁺ Kit Assay (Molecular Devices), based on a fluorescent calciumindicator and able to detect the calcium influx determined bydepolarizing conditions, was used for the assay. Differentiated cellswere incubated with dye loading for 30 minutes at 37° C. then,nifedipine alone (1 μM) or in the presence of ω-conotoxin (as referencestandard) or test compounds were added for further 15 minutes.

The fluorescence (excitation: 485 rn, emission: 535 nm wavelength) wasmeasured before and after (30-40 s) the automated injection of 100 mMKCl depolarizing solution using a Victor plate reader (Perkin Elmer).

The inhibition curves were calculated from 5 concentrations, each intriplicate, and the IC₅₀ determined using a linear regression analysis.

The compounds of the present invention inhibit N-type calcium channelswith pharmacologically significant IC₅₀ values.

The results obtained with some compounds, which are representative ofthe entire class of compounds of the invention, compared with theinternal standard ralfinamide, are reported in Table 1.

TABLE 1 IC₅₀ COMPOUND [μM]2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2- 2.6ylmethyl)amino]-N-(2-amino-2-methyl-propyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 2.1(cyclopropylmethyl)amino]-N-methyl-acetamide hydrochloride2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]- 6.01-(morpholin-4-yl)-2-phenyl-ethanone hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 4.8isobutylamino]-N-methyl-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 2.2benzylamino]-1-(pyrrolidin-1-yl)-ethanone hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 2.6benzylamino]-N-(2-amino-2-methyl-propyl)-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 1.9benzylamino]-N-(2-dimethylamino-ethyl)-acetamide dihydrochloride2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2- 1.9ylmethyl)amino]-N-(2-dimethylamino-ethyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 1.1benzylamino]-N,N-dimethyl-acetamide hydrochloride(S)-(+)-2-[4-(2-Fluoro-benzyloxy)-benzylamino]-propanamide 23(ralfinamide)

Data expressed as IC₅₀ values at μM concentration demonstrate that thecompounds of the invention are highly potent as inhibitors of N-typecalcium channels.

Example 106 L-Type Calcium Channel Influx Assay

AtT20/D16v-F2 mouse pituitary tumour cell line preferentially expressesL-type calcium channels. The remaining N-type calcium channels wereblocked using the selective N-type blocker co-conotoxin. In theseexperimental conditions only L type channels can be detected. AtT20cells were grown in DMEM with 10% of FBS, 4 mM glutamine. The cells wereseeded at 200,000 cells/well on 96 poly-L-lysine-coated plates andfurther incubated for 18-24 h, before use.

The Ca⁺⁺ Kit Assay (Molecular Devices), which is based on a fluorescentcalcium indicator to detect the calcium influx determined bydepolarizing conditions, was used for the assay. Cells were incubatedwith the calcium dye loading for 30 min at 37° C. Then, co-conotoxinalone (1 μM) or in presence of nifedipine (as reference standard) ortest compound were added for further 15 min.

The fluorescence (excitation: 485-emission: 535 nm wavelength) wasmeasured before and after (30-40 sec) the automated injection of 100 mMKCl depolarizing solution using a Victor plate reader (Perkin Elmer).

The inhibition curves were calculated from 5 concentrations, each intriplicate, and the IC₅₀ determined using a linear regression analysis.

The results, obtained with some compounds which are representative ofthe entire class of compounds of the invention, compared with theinternal standard ralfinamide, are reported in Table 2.

TABLE 2 IC₅₀ COMPOUND [μM]2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2- 2.9ylmethyl)amino]-N-(2-amino-2-methyl-propyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 3.8(cyclopropylmethyl)amino]-N-methyl-acetamide hydrochloride2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1- 7.1(morpholin-4-yl)-2-phenyl-ethanone hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 3.1isobutylamino]-N-methyl-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 1.6benzylamino]-1-(pyrrolidin-1-yl)-ethanone hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 2.4benzylamino]-N-(2-amino-2-methyl-propyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 1.2benzylamino]-N-(2-dimethylamino-ethyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 1.8(cyclopropylmethyl)amino]-N-ethyl-acetamide hydrochloride(S)-2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]- 1.0ethylamino]-N-methyl-4-methyl-valeramide2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(furan- 1.73-ylmethyl)amino]-N-methyl-acetamide hydrochloride2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2- 3.4ylmethyl)amino]-N-(2-dimethylamino-ethyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 4.6benzylamino]-N,N-dimethyl-acetamide hydrochloride(S)-(+)-2-[4-(2-Fluoro-benzyloxy)-benzylamino]-propanamide 26(ralfinamide)

Data expressed as IC₅₀ values at μM concentration demonstrate that thecompounds of the invention significantly interfere with L-type calciumchannels.

Example 107 TTXs-Sodium Channel Influx Assay

ND7/23 rat dorsal root ganglion-derived cell line endogenously expressesa mixed population of TTXs sodium channels (such as Nav1.3, Nav1.2,Nav1.1, Nav1.6). These cells lack of TTXr sodium channels as shown bythe absence of their respective transcripts.

ND7/23 cells were grown in DMEM supplemented with 10% FBS and 1 mMsodium piruvate.

The cells were seeded at 50,000 cells/well on 96 poly-L-lysine-coatedplates and further incubated for 18-24 h before use.

The Membrane Potential Kit Assay (Molecular Devices), based on anegatively charged fluorescent dye able to monitor changes in membranepotential caused by the sodium influx due to the channel opening, wasused for the assay.

Cells were incubated with the dye loading for 30 minutes at 25° C. Then,100 nM of the toxin Anemonia sulcata (used as enhancer of the channelopener response) alone or in the presence of TTX (as reference standard)or test compound were added for further 15 minutes.

The fluorescence (excitation: 530 nm, emission: 565 nm wavelength) wasmeasured before and after (40-45 s) the automated injection of thesodium channel opener veratridine (100 μM) using a Victor plate reader(Perkin Elmer).

The inhibition curves were calculated from 5 concentrations, each intriplicate, and the IC₅₀ determined using a linear regression analysis.

The compounds of the present invention inhibit TTXs sodium channels withpharmacologically significant IC₅₀ values.

The results, obtained with some compounds which are representative ofthe entire class of compounds of the invention, compared with theinternal standard ralfinamide, are reported in Table 3.

TABLE 3 IC₅₀ COMPOUND [μM]2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1- 2.1(morpholin-4-yl)-2-phenyl-ethanone hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 1.2benzylamino]-N-ethyl-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 3.5(cyclopropylmethyl)amino]-N-methyl-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(6- 2.9methoxy-pyridin-3-ylmethyl)amino]-N-methyl-acetamide2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3- 2.0ylmethyl)amino]-N,N-dimethyl-acetamide hydrochloride(S)-(+)-2-[4-(2-Fluoro-benzyloxy)-benzylamino]-propanamide 9.5(ralfinamide)

Example 108 Patch Clamp Studies of Calcium Currents Inhibition Cells andMethods:

Functional inhibition of the N-type Ca currents was studied using wholecell patch clamp methods (Hamill O. P., Marty A., Neher E., Sakmann B.,Sigworth F. J. Pflugers Arch. (1981) 391: 85-100) on HEK293 cellsexpressing recombinant human N-type channels, obtained after transienttransfection of h α1B (hCav2.2)+β1b+α2δ-1 subunits.

Membrane currents were recorded and filtered at 5 kHz with an AxonAxopatch 200B amplifier and digitized with an Axon Digidata 1322A (AxonInstruments, CA, USA). Voltage clamping of membrane potentials and dataacquisition were controlled online with Axon pClamp8 software. Measuringand reference electrodes were AgCl—Ag electrodes. Cells had initial sealresistances of >1 GΩ and access resistances of 4.2±0.2 MΩ. Cells werecontinuously superfused with extracellular solutions using a BiologicRSC-200. For calcium currents recording the control bath solutioncontained (mM): Choline chloride (70), MgCl₂ (1), BaCl₂ (20), TEA.Cl(50), Hepes (10), Glucose (10). Internal pipette solution consisted of(mM): CsCl (140), EGTA (10), MgCl₂ (2), Hepes (10), MgATP (1), GTP Tris(0.3).

Compounds were dissolved as 20 mM stock solutions in DMSO and thendiluted to the final concentration in the external solutions.

Voltage Protocols and Data Analyses:

A two-step protocol was used to determine the voltage dependence of theblock:

N-type current was activated by a 600 ms step pulse to +10 mV (testpulse) from a 5000 ms preconditioning potential of −110 mV (restingcondition) or −50/−55 mV (half maximal steady-state inactivatedcondition), respectively.

The amplitude of calcium current peaks evoked by the respective testpulses at a frequency of 0.06 Hz were measured before and after exposureto the test substance. Tonic block of currents was calculated as thedifference between the peak calcium current measured at the end of astabilization period in the control external bath solution and peakcurrents measured at the end of test substance perfusion period (whensteady state is reached) divided by control peaks. Drugconcentration-inhibition curves were obtained by plotting tonic blocksversus drug concentrations. Dose-response curves were fitted to thetonic block data, according to the logistic equation:y=A2+(A1−A2)/[1+(x/IC₅₀)^(p)]. A1 and A2 are fixed values of 0 and 1corresponding to 0 and 100% current inhibition, x is the drugconcentration, IC₅₀ is the drug concentration resulting in 50% currentinhibition and p is the corresponding slope factor.

The compounds of the present invention inhibit N-type calcium channelswith pharmacologically significant IC₅₀ values.

The results, obtained with some compounds, which are representative ofthe entire class of compounds of the invention, compared with theinternal standard ralfinamide, are reported in Table 4.

TABLE 4 IC₅₀ [μM] COMPOUND (Ihalf)2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 5.2(cyclopropylmethyl)amino]-N-methyl-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 11(tetrahydrofuran-3-ylmethyl)amino]-N-methyl-acetamide hydrochloride(S)-(+)-2-[4-(2-Fluoro-benzyloxy)-benzylamino]-propanamide 15(ralfinamide)

Data expressed as IC₅₀ values at μM concentration demonstrate that thecompounds of the invention are highly potent as inhibitors of N-typecalcium channels.

Example 109 Patch Clamp Studies of Sodium Currents Inhibition

Cells and methods: Functional inhibition of the sodium currents wasstudied using whole cell patch clamp methods (Harnill O. P., Marty A.,Neher E., Sakmann B., Sigworth F. J., Pflugers Arch. (1981) 391 (2):85-100) on HEK293 cells expressing recombinant Nav 1.3 channels.

Membrane currents were recorded as described in the example above.

For sodium current recording control bath solution contained (mM): NaCl(80), Choline chloride (38), CaCl₂ (1.3), MgCl₂ (2), KCl (2), CdCl₂(0.4), NiCl₂ (0.3), TEA.Cl (20), Hepes (10), Glucose (10). Internalpipette solution consisted of (mM): EGTA (10), NaCl (10), CaCl₂ (1.3),MgCl₂ (2), Hepes (10), CsF (130), MgATP (1).

Compounds were dissolved as 20 mM stock solutions in DMSO and thendiluted to the final concentration in the external solutions.

Voltage protocols and data analyses: A two-step protocol was used todetermine the voltage dependence of the block:

sodium current was activated by a 30 ms step pulse to 10 mV (test pulse)from a 2000 ms preconditioning potential of −100 mV (resting condition)or −50 mV (half maximal steady-state inactivated condition),respectively.

The amplitude of sodium current peaks evoked by the respective testpulses at a frequency of 0.06 Hz were measured before and after exposureto the test substance. Tonic block of currents was calculated as thedifference between the Nacurrent peak measured at the end of astabilization period in the control external bath solution and thecurrent peak measured at the end of test substance perfusion period(when steady state is reached) divided by control peaks. Drugconcentration-inhibition curves were obtained by plotting tonic blocksversus drug concentrations. Dose-response curves were fitted to thetonic block data, according to the logistic equation:y=A2+(A1−A2)/[1+(x/IC₅₀)^(p)]. A1 and A2 are fixed values of 0 and 1corresponding to 0 and 100% current inhibition, x is the drugconcentration, IC₅₀ is the drug concentration resulting in 50% currentinhibition and p is the corresponding slope factor.

The compounds of the present invention inhibit sodium channels withpharmacologically significant IC₅₀ values.

The results, obtained with compounds which are representative of theentire class of compounds of the invention, compared with the internalstandard ralfinamide, are reported in Table 5.

TABLE 5 IC₅₀ [μM] COMPOUND (Ihalf)2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 9.8(cyclopropylmethyl)amino]-N-methyl-acetamide hydrochloride2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3- 3.1ylmethyl)amino]-N,N-dimethyl-acetamide hydrochloride(S)-(+)-2-[4-(2-Fluoro-benzyloxy)-benzylamino]-propanamide 15(ralfinamide)

Data expressed as IC₅₀ values at μM concentration demonstrate that thecompounds of the invention are potent as inhibitors of sodium channels.

Example 110 Inhibition of Sodium Currents in Cortical Neurons

Cell Preparation and culturing: cortical neurons were prepared fromembryonic Wistar rats (E17-E19). Brains of E17/E19 rats were removed andplaced in ice-cold Hank's solution (Hank's solution(Life tech.14170-088)+glucose 30%+Pen-Strep 100×(Life Tech. 15140-122) 100 U-100μg/ml and Hepes-NaOH 5 mM).

Cortex were isolated, cut in small parts and washed twice with Hank'ssolution. The solution was removed except 1-2 ml and the tissue wasmechanically dissociated. After the mechanical dissociation, 5 ml ofcomplete DMEM (Dulbecco's modified Eagle medium) (Gibco 41966-029)+FBS(Hyclone) 10%+Glutamine (Life Tech. 25030-024) 2 mM+Pen-Strep 100 U-100μg/ml were added, and cell suspension was centrifuged for 5 min at 1000rpm. Supernatant was removed and 5 ml of complete Neurobasal medium wasadded (Neurobasal medium (Life tech. 21103-049)+B27 (Life tech.17504-044) 2%+Glutamine 2 mM+Pen-Strep 100 U-100 μg/ml).

Cells were counted and diluted in Neurobasal medium to a concentrationof 400000 cells per poly-D-lysine 5 μg/ml treated Petri dish.

Cortical neurons were used from day 6^(th) till day 11^(th) afterplating, and once a week Neurobasal medium was changed.

Whole Cell Patch Clamp Recordings: Experiments on cortical neurons werecarried out using standard whole cell patch clamp methods (Hamill etal., 1981). Membrane currents were recorded and filtered at 5 kHz withan Axon Axopatch 200B amplifier and data digitized with an Axon Digidata1322A (Axon Instruments, CA, USA). Protocol playing and data acquisitionwere controlled online with Axon pClamp8 software. Measuring andreference electrodes were AgCl—Ag electrodes. A Sutter Instrument P-87Puller (CA, USA) was used for pulling patch clamp pipettes with aresistance of 2-3 MΩ from Harward borosilicate glass tubes. Cells werecontinuously superfused with extracellular solutions, using a solutionchanger Biologic RSC-200.

Solutions: Sodium current recording control bath solution contained(mM): NaCl 60, CholineCl 60, CaCl₂1.3, MgCl₂2, KCl 2, CdCl₂0.4,NiCl₂0.3, TEACl 20, Hepes 10, Glucose 10. Internal pipette solutionconsisted of (mM): CsF 65, CsCl 65, NaCl 10, CaCl₂1.3, MgCl₂2, Hepes 10,EGTA 10, MgATP 1.

Voltage protocols and data analyses: cells were clamped at −90 mV, thena two step protocol was used to determine the voltage dependence of theblock. Sodium currents were activated by a 30 ms step pulse to −10 mV(test pulse) from a 200 ms preconditioning potential of −110 mV (restingcondition) and a potential of ˜−50 mV (half maximal steady-statecondition).

Drug concentration-inhibition curves were obtained by plotting tonicblocks in the resting and depolarized condition, versus drugconcentrations. Dose-response curves were fitted to the tonic blockdata, according to the logistic equation: y=A2+(A1−A2)/[1+(x/IC₅₀)p]. A1and A2 are fixed values of 0 and 1 corresponding to 0 and 100% currentinhibition, x is the drug concentration, IC₅₀ is the drug concentrationresulting in 50% current inhibition and p is the corresponding slopefactor.

The compounds of the present invention inhibit sodium currents ofcortical neurons with pharmacologically significant IC₅₀ values.

The results, obtained with compounds which are representative of theentire class of compounds of the invention, compared with the internalstandard ralfinamide, are reported in Table 6.

TABLE 6 IC₅₀ [μM] COMPOUND (Ihalf)2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3- 0.5ylmethyl)amino]-N,N-dimethyl-acetamide hydrochloride(S)-(+)-2-[4-(2-Fluoro-benzyloxy)-benzylamino]-propanamide 9(ralfinamide)

Example 111 In Vitro MAO-A and MAO-B Enzyme Activities Assay MembranePreparations (Crude Mitochondrial Fraction)

Male Wistar rats (Harlan, Italy—175-200 g) were sacrificed under lightanaesthesia and brains were rapidly removed and homogenized in 8 volumesof ice-cold 0.32 M sucrose buffer containing 0.1 M EDTA, pH 7.4. Thecrude homogenate was centrifuged at 2220 rpm for 10 minutes and thesupernatant recovered. The pellet was homogenized and centrifuged again.The two supernatants were pooled and centrifuged at 9250 rpm for 10minutes at +4° C. The pellet was resuspended in fresh buffer andcentrifuged at 11250 rpm for 10 minutes at +4° C. The resulting pelletwas stored at −80° C.

In Vitro Enzyme Activities Assay

The enzyme activities were assessed with a radioenzymatic assay usingthe substrates ¹⁴C-serotonin (5-HT) and ¹⁴C-phenylethylamine (PEA) forMAO-A and MAO-B, respectively. The mitochondrial pellet (500 μg protein)was resuspended in 0.1 M phosphate buffer (pH 7.4). 500 μl of thesuspension were added to a 50 μl solution of the test compound orbuffer, and incubated for 30 min at 37° C. (preincubation) then thesubstrate (50 μl) was added. The incubation was carried out for 30minutes at 37° C. (¹⁴C-5-HT, 5 μM) or for 10 minutes at 37° C. (¹⁴C-PEA,0.5 μM).

The reaction was stopped by adding 0.2 ml of 37% HCl or perchloric acid.After centrifugation, the deaminated metabolites were extracted with 3ml of diethyl ether (5-HT) or toluene (PEA) and the radioactive organicphase was measured by liquid scintillation spectrometry at 90%efficiency. The amount of neutral and/or acidic metabolites formed as aresult of MAO activity was obtained by measuring the radioactivity ofthe eluate.

The activity of MAO in the sample, corresponding to a percentage ofradioactivity compared with the control activity in the absence of theinhibitor, was expressed as nmoles of substrate transformed/mgprotein/min.

The results, as far as the MAO-B inhibition is concerned, obtained withsome compounds which are representative of the entire class of compoundsof the invention, are reported in Table 7.

TABLE 7 % Inhibition MAO-B at COMPOUND 100 μM2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2- 31ylmethyl)amino]-N-(2-amino-2-methyl-propyl)-acetamide dihydrochloride2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]- 0N,N-dimethyl-2-phenyl-acetamide hydrochloride2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]- 01-(morpholin-4-yl)-2-phenyl-ethanone hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 53isobutylamino]-N-methyl-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 11benzylamino]-1-(pyrrolidin-1-yl)-ethanone hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 32benzylamino]-N-(2-amino-2-methyl-propyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 33benzylamino]-N-(2-dimethylamino-ethyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 39benzylamino]-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]- acetamidedihydrochloride 2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-34 ylmethyl)amino]-N-(2-dimethylamino-ethyl)-acetamide dihydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 3.0benzylamino]-N,N-dimethyl-acetamide hydrochloride2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]- 4.0benzylamino]-N-ethyl-acetamide hydrochloride(S)-(+)-2-[4-(3-Fluoro-benzyloxy)-benzylamino]-propanamide 100(safinamide)

Data expressed as percentage of MAO-B inhibition observed in thepresence of 100 μM of compound, demonstrate that the compounds of theinvention are weak inhibitors of MAO-B, if compared with the internalstandard safinamide.

Example 112 Complete Freund's Adjuvant Model of Chronic InflammatoryPain

Monoarthritis was induced in rats (200 g weight) by an intra-plantarinjection into the left hind paw of 100 μl of complete Freund's adjuvant(CFA) containing heat-killed and dried Mycobacterium tubercolosis in amixture of paraffin oil and an emulsifying agent, mannide monooleate.The CFA injection produced an area of localized edema and inflammationstarting from few h after injection, with a progressive reduction in themechanical withdrawal threshold.

Each animal was allowed to develop the arthritis over a period of 8-9days before testing.

Mechanical Allodynia

Mechanical allodynia thresholds were determined according to the methodof Chaplan et al. (Chaplan S. R., Bach F. W., Pogrel J. W., Chung J. M.,Yaksh T. L. J Neurosci Methods (1994) 53: 55-63). Rats were placed inindividual plastic boxes of 24×10×15 cm on a mesh metal floor andallowed to acclimate for about 30 minutes before testing. A series ofcalibrated von Frey hairs (Stoelting, Wood Dale, Ill.) withlogarithmically incremental stiffness ranging from 2.83 to 5.88expressed Log₁₀ of [10× force in (mg)] were applied to the paw with amodified up-down method (Dixon W. J. Am. Stat. Assoc. (1965) 60:967-978). In the absence of a paw withdrawal response to the initiallyselected hair, a thicker hair corresponding to a stronger stimulus waspresented until a sharp withdrawal was recorded. The procedure wasrepeated twice. Each hair was presented perpendicularly against the paw,with sufficient force to cause slight bending, and held 2-3 s. Thestimulation of the same intensity was applied five/six times to the hindpaw at intervals of few sec. The mechanical threshold was expressed asLog₁₀ of [10× force in (mg)] indicating the force of the Von Frey hairto which the animal react (paw withdrawn, licking or shaking).

The mechanical allodynia thresholds were measured before (pre-drug) andat 30, 60, 90, 120, 240 and 360 minutes after the treatment. A 24 hthreshold was also measured.

The compounds of the invention were administered in a range of doses of0.1-100 mg/kg.

Example 113 Bennett Model of Neuropathic Pain in Rats

Effects on neuropathic pain are tested in the chronic constrictioninjury model in the rat (Bennett, G. J. and Xie, Y. K., A peripheralmononeuropathy in rat that produces disorders of pain sensation likethose seen in man, Pain, 33 (1988) 87-107). Under pentobarbitalanesthesia (Nembutal, 50 mg/kg, i.p.), unilateral multiple ligations areperformed on male SpragueDawley rats (140-160 g) at the right commonsciatic nerve. The sciatic nerve is exposed by blunt dissection at thelevel of mid-thigh and four loose ligatures (5-0 chromic catgut) areplaced around the nerve taking care not to interrupt the epineuralcirculation. After operation, animals are allowed to recover for oneweek. Animals develop a cold allodynia which is stable for at least fiveweeks. Cold allodynia is tested on a metal plate cooled by a water bathto a constant temperature of 4° C. The animals, randomly assigned togroups of 10 for each test dose and vehicle, are observed for periods of2 minutes before and after application of test compound and the numberof brisk withdrawal reactions is counted. Several time points afterapplication are tested. Percent maximal possible effect (% MPE) andstandard error of the mean (SEM) of each time point is determined withthe pre-test value used as 100% MPE. The area under the data (AUD) iscalculated for the observation period and expressed as percentinhibition of vehicle control as shown in Table 8. Significance iscalculated by paired t-test on the percent AUD values.

TABLE 8 Change vs. Dose Control COMPOUND [mg/kg] p.o. [%]2-[[2-(3-Butoxy-phenyl)-ethyl]- 0.1 35.7(tetrahydrofuran-3-ylmethyl)amino]-N,N- dimethyl-acetamide hydrochloride(S)-(+)-2-[4-(2-Fluoro-benzyloxy)- 1.0 23.7 benzylamino]-propanamide(ralfinamide)

Example 114 Maximal Electroshock Test (MES) in Mice

The maximal electroshock test (MES) is used commonly in the screening ofanti-epileptic drugs in rodent models.

Animals and Apparatus: Male CD1 mice weighing 25 g were used. Theprocedure described by White et al. (White H. S., Woodhead J. H.,Franklin M. R., Swinyard E. A., and Wolf H. H. Antiepileptic Drugs(1995) 4th ed: 99-110, Raven Press, Ltd., New York) was followed. An UgoBasile electroconvulsive generator (Model ECT UNIT 7801) was used todeliver an electrical stimulus sufficient to produce a hindlimb tonicextensor response in at least 97% of control animals. The stimulus wasdelivered intra-aurally through clip electrodes in mice (0.7 s of a 40mA shock, with a pulse train of 80 Hz having a pulse duration of 0.4ms). The acute effect of compounds administered intraperitoneally ororally 15-60 minutes before MES induction were examined and comparedwith a vehicle control group. Ten mice were studied per group. Completesuppression of the hindlimb tonic extensor component of seizures wastaken as evidence of anticonvulsant activity.

The compounds of the invention were administered i.v., orally orintraperitoneally at the doses of 0.1-100 mg/kg.

The results, obtained with a compound representative of the entirechemical class of the invention, administered i.v., 5 minutes beforetesting, compared with the internal safinamide, and reported in Table 9,demonstrate that these compounds are active as anticonvulsant drugs.

TABLE 9 COMPOUND 50% Protection2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3- (0.8 mg/kg/iv)ylmethyl)amino]-N,N-dimethyl-acetamide hydrochloride(S)-(+)-2-[4-(3-Fluoro-benzyloxy)-benzylamino]- (4.0 mg/kg/iv)propanamide (safinamide)

Example 115 Amphetamine and Chlordiazepoxide-Induced Hyperlocomotion inMice

In this model, mice are treated with a mixture of d-amphetamine plus ananxiolytic dose of the benzodiazepine, chlordiazepoxide (Rushton R,Steinberg H. Combined effects of chlordiazepoxide and d-amphetamine onactivity of rats in an unfamiliar environment. Nature 1966; 211:1312-3;R. Arban, G. Maraia, K. Brackenborough, L. Winyard, A. Wilson, P.Gerrard, C. Large. Evaluation of the effects of lamotrigine, valproateand carbamazepine in a rodent model of mania Behavioural Brain Research,158: 123-132). The model has been claimed to mimic some aspects of maniain bipolar disorder. Importantly, the hyperactivity induced by themixture of d-amphetamine and chlordiazepoxide could be prevented byprior administration of the established mood stabilizer, lithium, aswell as other mood stabilizers drugs (e.g. magnesium valproate andcarbamazepine). Therefore, this model has face and predictive validityas a model of bipolar disorder and represents a valuable tool todetermine, if a test compound could be a potential mood stabilizer drugcandidate. Amphetamine (AMP) (2.5 mg/kg) plus chlordiazepoxidehydrochloride (CDZ) (3 mg/kg/ip) were administered to male Albino Swissmice (25-32 g) in a volume of 10 ml/kg. The locomotor activity wasrecorded using Opto-M3 System (Columbus Instruments) which ismulti-channel activity monitor. Opto-M3 system has 10 infrared emittersand respective amount of receivers (0.5″ beam spacing), attached to thePC computer and calculating both ambulatory activity and total counts.Thus the system differentiates forward locomotion (ambulation) fromstereotyped like movement (total counts). Mice were pretreated with thetest compound (5 mg/kg) and 10 min later, with AMP (2.5 mg/kg) or AMPjointly with CDZ (3 mg/kg). After successive 30 min. the mice weretreated again with the same dose of the test compound and were placedindividually in the motor activity cages. The locomotor activity(ambulation and total activity count) was evaluated for 30 min. Eachgroup consisted of 8-10 mice.

Statistical analysis: the data were evaluated by an analysis of variance(ANOVA), followed, when appropriate, by individual comparison with thecontrol using Dunnett's test. Amphetamine-chlordiazepoxideadministration induced a significant increase in locomotor activity.

The effect of the compound2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamidehydrochloride, representative of the entire chemical class of thisinvention, was assessed as its capacity of preventing theamphetaminechlordiazepoxide induced increase in locomotor activity asshown in FIG. 1.

Example 116 Cognitive Impairment in Schizophrenia Method

Cognitive impairment is often associated with schizophrenia and it hascome to be recognized as a core element of the disorder, bearing onpatient's recovery and re-integration into society.

Particular interest has recently attracted a pharmacological model ofcognitive dysfunctions in schizophrenia, which is based on the effectsof glutamate NMDA receptor antagonists such as phencyclidine (PCP) andketamine (Javitt et al., 1991) which impair attention and increase“impulsivity” and “compulsive” perseveration in mice performing acomplex task (Greco et al., 2005).

Materials and Methods

Animals: Male DBA/2N mice (Charles River, Italy) were used. The miceweighed 25-30 g at the start of the experiments, and were housed undertemperature-controlled conditions (21° C.) with a 12 h light 12 h darkcycle (light on 7:00 am-7:00 pm). Food (Rieper, Italy) was available adlibitum. The animals had two hours of access to water at the end of eachday's testing.

The five-choice serial reaction time task apparatus: The test apparatusconsisted of four 21.6×17.8×12.7 cm chambers (Med Associates Inc. USA),as previously described [Greco, 2005 #26]. Stimuli and recording ofresponses, were managed by a SmartCtrl™ Package 8 In/16 Out (MedAssociates Inc. USA) with additional interfacing by MED-PC for Windows(Med Associates Inc. USA). The running program for the 5-CSRT task wascustom-written.

Behavioural procedures: habituation to liquid reinforcer and nose-pokingin the holes. Mice were handled for one week and their body weightrecorded. They were then water-deprived by allowing them 2-h access towater in the early evening until their body weight had stabilised (8days). Then, over the next two days the mice were habituated in theirhome cages to the reinforcer (10% sucrose solution) used afterwards inthe operant procedures. On the following two days mice were habituatedto the operant boxes. During this stage, 10% sucrose solution wasavailable in a small bowl placed below the receptacle hole of the box.First, mice had to learn that every 5 sec the liquid reward wasavailable in a small cup in the receptacle hole. During this period headentries were recorded. During the next period, mice were trained to poketheir noses into the illuminated holes. Immediately after a poke in thewater receptacle a LED at the rear of one of the holes was turned on. Anose-poke in the lighted hole extinguished the light stimulus and theliquid dipper provided a 0.01 mL liquid reward in the receptacle hole.Any response in one of the other four holes had no consequence and wasnot recorded. The light stimulus was presented in all five holes inrandom order. A mouse was switched to the 5-CSRT task after it hadcompleted at least 50 rewarded nose-poke trials in one 30-min session.

The five-choice serial reaction time task. The start of the session wassignalled by illumination of the house-light and the delivery of a 0.01mL liquid reward. Nose poking in the receptacle hole began the firsttrial. After a fixed delay (the inter-trial interval, ITI), the LED atthe rear of one of the holes came on for a short period. The LEDstimulus was presented the same number of times in each hole during acomplete session, with the order of presentation randomised by thecomputer. While the light was on, and for a short period afterwards (thelimited hold), responses in the hole that was illuminated (correctresponse) resulted in the liquid reward. Responses in the holes that hadnot been illuminated (incorrect responses) or failure to respond withinthe limited hold (omissions) caused the house-lights to be turned offfor a short period (time out). Responses in the holes while thehouse-light was off restarted the time out. After the delivery of theliquid reward, or at the end of time out, the mouse started the nexttrial by poking its nose into the receptacle hole. Responses made in theholes after a correct response (perseverative responses), or after theend of time out before nose-poking into the receptacle hole, resulted ina period of time out. Responses in the holes during the ITI(anticipatory responses) also resulted in a period of time out. Afteranticipatory responses a nose-poke into the receptacle hole restartedthe current trial. Each daily session consisted of 100 trials or 30 minof testing, whichever was completed sooner, after which all lights wereturned off and further responses had no effect. In the first session ofthe test schedule, the stimulus and limited hold each lasted 1 min and,depending on individual performance, they were progressively reduced to1 sec. The stimulus duration was reduced in the following sequence: 60,30, 10, 5, 2.5, 2, 1.5 and 1 sec (baseline). The ITI and time out bothlasted 2 sec during the first session and the ITI was raised to 5 sec insubsequent sessions; time out was not changed. Throughout the wholeperiod of training and experiments each mouse had one session per day ona 5-CSRT task.

Drugs and treatment schedules. The test compound was dissolved in waterand was administered intraperitonealy (IP) at the dose of 10 mg/kg. Fiveminutes after the treatment mice were injected with vehicle (saline) orPCP (1.5 mg/kg) and 10 min later they started the test session. In eachexperiment the various combination of the test compound with vehicle orPCP were administered according to a Latin-square design. At least 48 hwere left between the drug testing days. During these intervening daysthe mice were tested on the 5-CSRT task to re-establish baselineperformance and to check for any residual effects of drugs.

Statistical analysis: The main dependent variables selected for analysiswere: (a) the percentage of correct responses (total correctresponses/total correct+total incorrect responses×100); (b) percentageof omissions (total omissions/total correct responses+total incorrectresponses+total omissions×100); (c) the number of anticipatory responsesin the holes during the ITI; (d) the number of perseverative responsesin the holes after a correct response. Correct responses and omissions,as percentages, were transformed according to the formula 2arcsin(SQRT(% X/100)), to normalize the distributions in accordance withthe ANOVA model (Winer, 1971).

The effects of the test compound (n=12) on PCP induced deficits in the5-CSRT task were analysed independently by a within subjects 2×2 ANOVAwith factors Drug (test compound) and PCP. Subsequently the treatmentgroup means were compared using a post-hoc TukeyKramer test. Statisticalsoftware (SAS Institute Inc., USA) was run on Micro VAX 3500 computer(Digital, USA).

As shown in table 10, PCP caused a profound effect on attentionalperformance of DBA/2N mice as shown by increased anticipatory andperseverative responses. A representative compound of our invention,administered 10 mg/kg i.p., can reverse PCP-induced increase inanticipatory and perseverative responses. These results support the useof this kind of compounds for the treatment of psychiatric disorders.

TABLE 10 N of No f anticipatory perseverative resposnses responses Veh +veh 1.8 ± 0.5 19.3 ± 14   2-[[2-(3-Butoxy-phenyl)-ethyl]- 3.3 ± 0.7 20.9± 1.3  (tetrahydrofuran-3-ylmethyl)amino]-N,N- dimethyl-acetamidehydrochloride 10 mg/Kg Veh + PCP 10.2 ± 2.8* 31.2 ± 5.8*2-[[2-(3-Butoxy-phenyl)-ethyl]-  3.7 ± 1.6# 15.7 ± 3.1#(tetrahydrofuran-3-ylmethyl)amino]-N,N- dimethyl-acetamide hydrochloride10 mg/Kg + PCP

Example 117 Cocaine-Induced Behavioural Sensitization Test

Drug addiction is a pathological behaviour characterized by compulsivedrug seeking and intake. One animal model of these behavioral changes isthe long-lasting increase in locomotor activity induced by repeatedadministration of psychostimulant drugs in rodents (Robinson T. E. andBerridge K. C. Brain Res. Brain Res. Rev. (1993) 18, 247-91) known asdrug-induced behavioural sensitization. The effect of test compoundswere evaluated in a model of cocaineinduced behavioral sensitization inrat.

Locomotor activity apparatus: Male Wistar rats weighing 200-250 g uponarrival were used. Locomotor activity was measured in sixteen identicalmetal wire hanging cages each measuring 36 cm (L)×25 cm (W)×20 cm (H).Each cage contained two sets of infrared emitter-detector photocellspositioned along the long axis 1 cm above the grid floor and 8 cm fromthe front and back of the cage. Background noise was provided by a whitenoise generator. Movement within the cages produced photocellinterruptions, which were automatically recorded by an IBM-compatiblecomputer.

Sensitization procedure and treatment: Animals were habituated to thelocomotor activity chambers for 2-3 consecutive days before theexperiment. Rats received 5 daily i.p. injections of cocaine (15 mg/kg)or saline and either the test compound (0.1-100 mg/kg) or its vehicleand locomotor activity was recorded for 3 h. Ten days after the lastinjection of cocaine or saline (day 15), the animals were challengedwith 15 mg/kg of cocaine in absence of the test compound and locomotoractivity was again monitored for 3 h.

By the fifth day of treatment with cocaine, animals pretreated i.p. withvehicle showed an increased locomotor response (20% higher then thefirst day, p<0.05). Ten days after the last injection of cocaine orsaline, the animals were challenged with 15 mg/kg of cocaine in absenceof the test compound and locomotor activity was again monitored for 3 h.The rats previously treated with cocaine and that had not received thetest compound are expected to show an increased locomotor activityresponse to cocaine (30% higher then first day, p<0.05). If the ratsthat had been pretreated with the test compound during the 5 day-cocainetreatment did not show an increase in locomotor activity the testcompound is considered to have an effect in preventing psychostimulantdrugs addiction. (Koob G. F., Sanna P. P., Bloom F. E. Neuron (1998) 21:467-476; Robinson T. E., Berridge K. C. Brain Res Brain Res Rev (1993)18: 247-291)

Statistical analysis: Data (total number of beam breaks in 3 hours) wereanalyzed using a two way ANOVA with repeated measures on one factorincluding the four experimental groups (i.e., saline/vehicle,saline/test compound, cocaine/vehicle and cocaine/test compound) and twotime points (day 1 and day 5) followed by a simple effects analysis. Asecond two way ANOVA with repeated measures on one factor was used tocompare day 1 and the challenge day followed by a Newman-Keuls post hoctest.

Example 118 Acute Bladder Irritation by Acetic Acid in Rats

Experiments were performed using adult anesthetized female SpragueDawley rats (170-200 g). A catheter (PE-50) was inserted via a midlineabdominal incision into the bladder through the bladder dome, and thenintravesical pressure was measured to monitor bladder activity duringcontinuous infusion of 0.15% af acetic acid. Continuous intravesicalinfusion of acetic acid irritates the bladder and reduces theintercontraction intervals (ICI) in anesthetized rats. ICIs, maximalcontraction pressure, and pressure thresholds inducing reflex bladdercontraction were measured before and after intravesical infusion ofacetic acid in rats treated with compounds of the invention.

Example 119 Intermediate Bladder Irritation by Cyclophosphamide (CYP) inRats

Experiments were performed using both adult awake and anesthetizedfemale Sprague Dawley rats (170-200 g). Chemical cystitis was induced byCYP, which is metabolized to acrolein, an irritant eliminated in theurine. CYP (150 mg/kg/i.p.) was administered one day before theexperiment. Pre-treatment with CYP causes bladder irritation and veryfrequent voidings with an ICI of about 150-200 seconds between voids.

Active compounds increase the ICI in both awake and anesthetized ratsused in this experimental model.

Example 120 Migraine Test in Rats

Animals and surgery: Male Wistar rats (250-350 g) were anesthetized withsodium pentobarbital (50 mg/kg i.p.) dissolved in saline. The tracheaand left femoral artery were cannulated for artificial ventilation (55strokes/min) and for measurement of mean blood pressure (MBP)respectively. The femoral vein was cannulated for the intravenousadministration of test agents.

Body temperature was maintained at 37-38° C. by automatic control of aheating pad. Animals were placed in a stereotaxic frame and alongitudinal incision was made in the scalp. A burr hole was drilled inthe skull and a stainless steel bipolar electrode (Plastic One MS 306)was lowered into left ophthalmic branch of the trigeminal ganglion (3.8mm dorsal to bregma, 2.5 mm lateral from the midline and 9.5 mm belowthe dural surface) and secured with dental cement. Correct placement ofthe electrode was confirmed by a brief electrical stimulation, whichcause movement of the jaw due to activation of the trigeminal fiber.Following removal of the brain, the correct position of the electrodeinto the fiber, was visually checked at the end of each experiment.

A second hole was drilled ipsilateral of the electrode (1.5 mm rostralto bregma, and 1.5 mm lateral from the sagittal suture) and a needleprobe (tip diameter 0.8 mm) of a laser doppler flowmeter was fixedpointing with its tip onto a branch of the middle cerebral artery (MCA)and Cerebral Blood Flow (CBF) change recorded on-line by the PeriFlux4001 Laser Doppler system.

Artefacts of the laser Doppler reading during electrical stimulation ofthe trigeminal ganglion due to muscular movements were prevented by abolus of i.v. injection of the neuromuscular blocker pancuronium bromide(0.6 mg/kg i.v.).

Anesthesia and neuromuscular blockade were maintained all over theexperiment with an infusion of sodium pentobarbital and pancuronium(12.5 mg/kg/h+2.4 mg/kg/h, respectively).

Experimental protocol: At the end of the surgery, a pause of thirtyminutes was taken in order to stabilize the measured parameters.

Rest CBF was increased by electrical stimulation with rectangular pulseof 0.5 ms length, 1-10 Hz, 0.5-1 mA for periods of 30 s. After twoaveraged pre-drug stimulations, vehicle or drugs were administered.

Active compounds reduce the increase in blood flow induced by trigeminalstimulation.

1. A compound of general formula I

wherein: (a) J is a group A-[(CH₂)_(n)—O]_(r)— in para position withrespect to the ethylamino chain wherein: n is zero or 1; and r is 1; Ais trifluoromethyl; or phenyl optionally substituted with a halo group;W is (C₁-C₄)alkoxy; R is hydrogen; R⁰ is hydrogen; or (C₁-C₂)alkyl; R¹is hydrogen; (C₁-C₄)alkyl optionally substituted with a hydroxy group;cyclopropylmethyl; 2-propyn-1-yl; benzyl optionally substituted with oneor two (C₁-C₂)alkoxy groups on the benzene ring; thiazolyl; a 5-6membered saturated heterocyclyl containing a nitrogen atom, optionallysubstituted with a (C₁-C₂)alkyl group; or heterocyclylmethyl wherein theheterocyclyl group is a 5-6 membered heterocyclyl containing 1 to 3hetero atoms selected from nitrogen, oxygen and sulfur, optionallysubstituted with one or two groups selected from (C₁-C₂)alkyl,hydroxymethyl and (C₁-C₂)alkoxy; R² is hydrogen; (C₁-C₄)alkyl; orphenyl; R³ is hydrogen; or (C₁-C₄)alkyl; and R⁴ is hydrogen;(C₁-C₄)alkyl optionally substituted with a group selected from amino,(C₁-C₄)alkylamino, di-(C₁-C₄)alkylamino, imidazolyl and pyrrolidinylwherein the imidazolyl and the pyrrolidinyl group is optionallysubstituted with a (C₁-C₂)alkyl group; or benzyl; or R₃ and R₄, takentogether with the adjacent nitrogen atom, form a pyrrolidinyl,morpholinyl or piperazinyl ring optionally substituted with a(C₁-C₂)alkyl group; or (b) J is hydrogen; W is a groupA-[(CH₂)_(n)—O]_(r)— wherein: n is zero, 1 or 2; and r is zero or 1; Ais (C₁-C₄)alkyl, trifluoromethyl; cyclopropyl; cyclopentyl; phenyloptionally substituted with a group selected from halo, methyl, methoxy,trifluoromethyl, acetylamino, and dimethylaminomethyl; thienyloptionally substituted with a chloro group; furanyl; isoxazolyloptionally substituted with one or two methyl groups; piperidinyl;morpholinyl; pyridinyl or pyrimidinyl, the pyridinyl and pyrimidinylring being optionally substituted with one or two methoxy groups; R ishydrogen; or fluoro; R⁰ is hydrogen; or (C₁-C₂)alkyl; R¹ iscyclopropylmethyl; furanylmethyl; tetrahydrofuranyl; ortetrahydrofuranylmethyl; R² is hydrogen; or (C₁-C₄)alkyl; R³ ishydrogen; or (C₁-C₄)alkyl; and R⁴ is hydrogen; (C₁-C₄)alkyl optionallysubstituted with a group selected from (C₁-C₂)alkoxy, amino,(C₁-C₄)alkylamino and di-(C₁-C₄)alkylamino; or heterocyclyl wherein theheterocyclyl is selected from isoxazolyl, pyrazolyl, imidazolyl,thiazolyl and 1,3,4 thiadiazolyl and may be optionally substituted witha (C₁-C₂)alkyl group; or R³ and R⁴ taken together with the adjacentnitrogen atom form a pyrrolidine ring; with the proviso that when A is(C₁-C₄)alkyl, trifluoromethyl, cyclopropyl or cyclopentyl, then r is 1;either as a single enantiomer (or diastereoisomer, as the case may be)or mixture thereof, or pharmaceutically acceptable salts of the singleenantiomer (or diastereomer) or mixture thereof.
 2. A compound of claim1, group (a) wherein: J is a group A-[(CH₂)_(n)—O]_(r)— in para positionwith respect to the ethylamino chain wherein: n is 1; and r is 1; A istrifluoromethyl; phenyl; or phenyl substituted with a fluoro or chlorogroup; W is methoxy; R is hydrogen; R⁰ is hydrogen; R¹ is hydrogen;(C₁-C₄)alkyl; hydroxyethyl; cyclopropylmethyl; 2-propin-1-yl; benzyloptionally substituted with one or two methoxy groups on the benzenering; piperidinyl optionally substituted with a methyl group; thiazolyl;or heterocyclylmethyl wherein the heterocyclyl group is selected fromisoxazolyl optionally substituted with a methyl or methoxy group,imidazolyl optionally substituted with a methyl group, furanyloptionally substituted with a hydroxymethyl group, tetrahydrofuranyl,1,2,3-thiadiazolyl, pyrazolyl optionally substituted with one or twomethyl groups, pyridinyl optionally substituted with a methoxy group,thienyl and thiazolyl; R² is hydrogen; (C₁-C₄)alkyl; or phenyl; R³ ishydrogen; or (C₁-C₄)alkyl; and R⁴ is hydrogen; (C₁-C₄)alkyl optionallysubstituted with a group selected from amino, dimethylamino, imidazolyland pyrrolidinyl wherein the pyrrolidinyl is optionally substituted witha methyl group; or benzyl; or R³ and R⁴ taken together with the adjacentnitrogen atom form a pyrrolidinyl, piperazinyl or morpholinyl ringoptionally substituted with a methyl group; either as a singleenantiomer (or diastereoisomer, as the case may be) or mixture thereof,or pharmaceutically acceptable salts of the single enantiomer (ordiastereomer) or mixture thereof.
 3. (canceled)
 4. A compound of claim1, group (b) wherein: J is hydrogen; W is a group A-[(CH₂)_(n)—O—]_(r)—wherein: n is zero, 1 or 2; r is zero or 1; A is (C₁-C₄)alkyl;trifluoromethyl; cyclopropyl; cyclopentyl; phenyl optionally substitutedwith a group selected from fluoro, chloro, methyl, methoxy,trifluoromethyl, acetylamino and dimethylaminomethyl; thienyl optionallysubstituted with a chloro group; furanyl; isoxazolyl optionallysubstituted with one or two methyl groups; piperidinyl; morpholinyl;pyridinyl or pyrimidinyl, the pyridinyl and pyrimidinyl group beingoptionally substituted with one or two methoxy groups; R is hydrogen; orfluoro; R⁰ is hydrogen; R¹ is cyclopropylmethyl; furanylmethyl;tetrahydrofuranyl; or tetrahydrofuranylmethyl; R² is hydrogen; ormethyl; R³ is hydrogen; or (C₁-C₄)alkyl; and R⁴ is hydrogen;(C₁-C₄)alkyl optionally substituted with a group selected from methoxy,amino, methylamino and dimethylamino; isoxazolyl optionally substitutedwith a methyl group; pyrazolyl; imidazolyl; thiazolyl; or 1,3,4thiazolyl; or R³ and R⁴ taken together with the adjacent nitrogen atomform a pyrrolidine ring; with the proviso that when A is (C₁-C₄)alkyl,trifluoromethyl, cyclopropyl or cyclopentyl, then r is 1; either as asingle enantiomer (or diastereoisomer, as the case may be) or mixturethereof, or pharmaceutically acceptable salts of the single enantiomer(or diastereomer) or mixture thereof.
 5. A compound of claim 4 wherein:J is hydrogen; W is a group A-[(CH₂)]_(n)—O]_(r)— wherein: n is 1 or 2;r is 1; A is (C₁-C₄)alkyl; trifluoromethyl; cyclopropyl; cyclopentyl;phenyl optionally substituted with a group selected from fluoro, chloro,methyl, methoxy, and trifluoromethyl; thienyl optionally substitutedwith a chloro group; isoxazolyl optionally substituted with one or twomethyl groups; pyridinyl; piperidinyl; or morpholinyl; R is hydrogen; orfluoro; R⁰ is hydrogen; R¹ is cyclopropylmethyl; furanylmethyl;tetrahydrofuranyl; or tetrahydrofuranylmethyl; R² is hydrogen; R³ ishydrogen; or (C₁-C₄)alkyl; and R⁴ is hydrogen; (C₁-C₄)alkyl optionallysubstituted with a group selected from methoxy, amino, methylamino anddimethylamino; isoxazolyl optionally substituted with a methyl group;pyrazolyl; imidazolyl; thiazolyl; or 1,3,4 thiazolyl; or R³ and R⁴ takentogether with the adjacent nitrogen atom form a pyrrolidine ring; eitheras a single enantiomer (or diastereoisomer, as the case may be) ormixture thereof, or pharmaceutically acceptable salts of the singleenantiomer (or diastereomer) or mixture thereof.
 6. A compound of claim4 wherein: J is hydrogen; W is a group A-[(CH₂)_(n)—O]_(r)— wherein: nis zero; r is 1; A is cyclopentyl; or phenyl optionally substituted witha fluoro group; R is hydrogen; R¹ is furanylmethyl; R² is hydrogen; R³is hydrogen; or (C₁-C₄)alkyl; and R⁴ is hydrogen; or (C₁-C₄)alkyl;either as a single enantiomer (or diastereoisomer, as the case may be)or mixture thereof, or pharmaceutically acceptable salts of the singleenantiomer (or diastereomer) or mixture thereof.
 7. A compound of claim4 wherein: J is hydrogen; W is a group A-[(CH₂)_(n)—O]_(r)— wherein: nis zero; r is zero; A is phenyl optionally substituted with a groupselected from fluoro, methoxy, acetylamino and dimethylaminomethyl;thienyl; furanyl; isoxazolyl optionally substituted with one or twomethyl groups; piperidinyl; pyridinyl or pyrimidinyl, the pyridinyl andpyrimidinyl group being optionally substituted with one or two methoxygroups; R is hydrogen; R⁰ is hydrogen; R¹ is furanylmethyl; ortetrahydrofuranylmethyl; R² is hydrogen; R³ is hydrogen; or(C₁-C₄)alkyl; and R⁴ is hydrogen; or (C₁-C₄)alkyl; either as a singleenantiomer (or diastereoisomer, as the case may be) or mixture thereof,or pharmaceutically acceptable salts of the single enantiomer (ordiastereomer) or mixture thereof.
 8. A compound of claim 5 wherein: J ishydrogen; W is a group A-[(CH₂)_(n)—O]_(r)— wherein: n is 1; r is 1; Ais (C₁-C₄)alkyl; R is hydrogen; R⁰ is hydrogen; R¹ is furanylmethyl; ortetrahydrofuranylmethyl; R² is hydrogen; R³ is hydrogen; or(C₁-C₄)alkyl; and R⁴ is (C₁-C₄)alkyl; either as a single enantiomer (ordiastereoisomer, as the case may be) or mixture thereof, orpharmaceutically acceptable salts of the single enantiomer (ordiastereomer) or mixture thereof.
 9. A compound of claim 1 selectedfrom:2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methylacetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-isobutylamino]-N-methyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N-methyl-acetamide;2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N,N-dimethyl-acetamide;2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-propionamide;2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-2-phenyl-acetamide;2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1-(morpholin-4-yl)-2-phenyl-ethanone;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-1-(pyrrolidin-1-yl)-ethanone;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-amino-2-methyl-propyl)-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-dimethylamino-ethyl)-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-ethyl-acetamide;2-[[2-[4-(Benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide;2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]N-methyl-acetamide;2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methylacetamide;2-[[2-[3-(2-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamide;2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-acetamide;2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-dimethylamino-ethyl)-acetamide;2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-amino-2-methyl-propyl)-acetamide;2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amino]-N-methylpropionamide;2-[[2-[3-Methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide;2-[[2-(3′-Fluoro-biphenyl-3-yl)-ethyl]-(furan-2-ylmethyl)amino]-N-methylacetamide;2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;2-[[2-[(3-Butoxy-phenyl)]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;2-[[2-(3-Butoxy-phenyl)-ethyl]-(furan-2-ylmethyl)amino]-N-methyl-acetamidehydrochloride;2-[[2-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;2-[[2-[3-(2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]N,N-dimethyl-acetamide;2-[[2-[3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide;2-[[2-(3-Piperidin-1-yl-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide;(S)-2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]N-methyl-4-methyl-valeramide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(furan-3-ylmethyl)amino]-N-methyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-ethylacetamide;and2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(6-methoxy-pyridin-3-ylmethyl)amino]-N-methyl-acetamide;either as a single enantiomer (or diastereoisomer, the case may be) ormixture thereof, or pharmaceutically acceptable salts of the singleenantiomer (or diastereomer) or mixture thereof.
 10. A compound of claim9 which is2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamideand its pharmaceutically acceptable salts.
 11. A compound of claim 10which is the single enantiomer having an [α]_(D)=−10°, c=0.1, MeOH (20°C.) or the single enantiomer having [α]_(D)=+10°, c=0.1, MeOH (20° C.)or a mixture thereof in any proportion and its pharmaceuticallyacceptable salts.
 12. A compound according to claim 1 wherein thepharmaceutically acceptable salt is the hydrochloride. 13-21. (canceled)22. A method for the treatment of a disorder caused by dysfunctions ofvoltage gated calcium and/or sodium channels in a patient, said methodcomprising administering to a patient in need thereof an effectiveamount of a calcium and/or sodium channel modulating amount of acompound of claim
 1. 23. A method as in claim 22 wherein the disorder isa neuropathic pain, chronic pain and/or acute pain disorder.
 24. Amethod as in claim 22 wherein the disorder is headache.
 25. A method asin claim 22 wherein the disorder is a cognitive and/or psychiatricdisorder.
 26. A method as in claim 22 wherein the disorder is aneurological condition such as epilepsy.
 27. A method as in claim 22wherein the disorder is an inflammatory process affecting any bodysystem, a disorder of the gastrointestinal tract, a disorder of thegenito-urinary tract, an ophthalmic disease, a liver disease, acardiovascular disorder caused by dysfunctions of voltage gated calciumand/or sodium channels, and/or a neurodegenerative disorder caused bydysfunctions of voltage gated calcium and/or sodium channels.
 28. Amethod as in claim 22, wherein the compound administered to the patientin need thereof is2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]N,N-dimethyl-acetamide,either as a single enantiomer or a mixture thereof, or apharmaceutically acceptable salt of the single enantiomer or mixture.29. A method according to claim 22 wherein the effective amount of thecompound administered to the patient in need thereof does not exhibitany MAO inhibitory activity or exhibits a significantly reduced MAOinhibitory activity, as compared to safinimide.
 30. A compound of claim1, group (a) wherein: J is a group A-[(CH₂)_(n)—O]_(r)— in para positionwith respect to the ethylamino chain wherein: n is 1; and r is 1; A isphenyl; or phenyl substituted with a fluoro group; W is methoxy; R ishydrogen; R⁰ is hydrogen; R¹ is hydrogen; (C₁-C₄)alkyl;cyclopropylmethyl; benzyl; or heterocyclylmethyl wherein theheterocyclyl group is selected from furanyl, tetrahydrofuranyl, andpyridinyl optionally substituted with a methoxy group; R² is hydrogen;(C₁-C₄)alkyl; or phenyl; R³ is hydrogen; or (C₁-C₄)alkyl; and R⁴ ishydrogen; (C₁-C₄)alkyl optionally substituted with a group selected fromamino, dimethylamino, and pyrrolidinyl wherein the pyrrolidinyl isoptionally substituted with a methyl group; or R³ and R⁴ taken togetherwith the adjacent nitrogen atom form a pyrrolidinyl or morpholinyl ring;either as a single enantiomer (or diastereoisomer, as the case may be)or mixture thereof, or pharmaceutically acceptable salts of the singleenantiomer (or diastereomer) or mixture thereof.
 31. A compound of claim9 selected from the group consisting of:2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-isobutylamino]-N-methyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N-methyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N,N-dimethyl-acetamide;2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N,N-dimethyl-2-phenyl-acetamide;2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-1-(morpholin-4-yl)-2-phenyl-ethanone;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-1-(pyrrolidin-1-yl)-ethanone;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-amino-2-methyl-propyl)-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-(2-dimethylamino-ethyl)-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-ethyl-acetamide;2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-dimethylaminoethyl)-acetamide;2-[[2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amino]-N-(2-amino-2-methyl-propyl)-acetamide;2-[[2-[(3-Butoxy-phenyl)]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-N-methyl-acetamide;(S)-2-[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-N-methyl-4-methyl-valeramide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(furan-3-ylmethyl)amino]-N-methyl-acetamide;2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamino]-N-ethylacetamide;and2-[[2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(6-methoxy-pyridin-3-ylmethyl)amino]-N-methyl-acetamide;either as a single enantiomer (or diastereoisomer, as the case may be)or mixture thereof, or pharmaceutically acceptable salts of the singleenantiomer (or diastereomer) or mixture thereof.
 32. A pharmaceuticalcomposition comprising a compound of claim 1 as active agent and apharmaceutically acceptable excipient.
 33. The pharmaceuticalcomposition of claim 32, further comprising a second active agent.
 34. Apharmaceutical composition of claim 32, wherein the compound of claim 1is2-[[2-(3-Butoxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide,either as a single enantiomer or a mixture thereof, or pharmaceuticallyacceptable salts of the single enantiomer or mixture thereof.